Neuropsychology
2010, Vol. 24, No. 1, 9 –34
© 2010 American Psychological Association
0894-4105/10/$12.00 DOI: 10.1037/a0017336
Association Between Depression Severity and Neurocognitive Function in
Major Depressive Disorder: A Review and Synthesis
Shawn M. McClintock
Mustafa M. Husain, Tracy L. Greer,
and C. Munro Cullum
University of Texas Southwestern Medical Center at Dallas
and Columbia University
University of Texas Southwestern Medical Center at Dallas
The effects of major depressive disorder (MDD) on neurocognitive function remain poorly understood.
Results from published studies vary widely in terms of methodological factors, and very little is known
about the effects of depression severity and other clinical characteristics on neurocognitive function. The
purpose of this review was to synthesize prior research findings regarding neurocognitive functioning in
patients with MDD and varying levels of depression severity and to provide recommendations for future
directions. Overall, this review suggests that MDD has been inconsistently associated with neurocognitive functioning and there is limited understanding regarding the relationship between depression severity
and neurocognitive sequelae. There was much heterogeneity on depression severity-related factors across
studies assessing neurocognitive function in MDD, as well as substantial variability in the consideration
of depression severity among studies, which suggests a need to further explore this important issue.
Keywords: major depressive disorder, neuropsychology, depression severity, neurocognitive function
episodic memory (mean effect size, Cohen’s d ⫽ 0.73) and attention (mean effect size ⫽ 0.59) were the cognitive domains that
tended to be most affected by depression. Moreover, neurophysiological studies have implicated the role of the prefrontal cortex
and the hippocampus in MDD (Elliott, Rubinsztein, Sahakian, &
Dolan, 2002; Schatzberg, 2002). However, there has been considerable variability in methodologies across studies thereby contributing to some of the inconsistencies in the neurocognitive associated effects of depression.
The purpose of this review was to synthesize prior research
findings regarding associations between depression severity and
neurocognitive functioning in MDD, and further to provide recommendations for future directions. To accomplish a systematic
literature review (Wright, Brand, Dunn, & Spindler, 2007), we
searched the PsychInfo and Medline databases (English language
literature, 1980 to 2008; OvidSP, Ovid Technologies, Inc.) with
the following terms (e.g., OvidSP subject headings): major depressive disorder and neuropsychology. To control for duplicate information and redundancy, the results were imported and managed
with Endnote (Version ⫻ 2 for Mac, The Thomson Corp., New
York, NY). When we encountered studies with overlapping participant samples, the studies with the smaller sample sizes were
excluded from consideration. A total of 35 studies (see Table 1)
that focused on depression severity were included in this review.
These studies were published between 1991 and 2007, from multiple countries of origin (Australia, Belgium, Canada, Denmark,
France, Germany, Israel, New Zealand, Norway, Sweden, United
Kingdom, United States), and the sample sizes ranged from 40 to
420 (M ⫽ 113.4, SD ⫽ 85.2).
It has long been noted that major depressive disorder (MDD)
can negatively affect neurocognitive function (Schatzberg, 2002;
Shenal, Harrison, & Demaree, 2003; Zakzanis, Leach, & Kaplan,
1999). The majority of studies have focused on MDD collectively
in relation to cognitive functioning, and in addition to sampling
differences, many do not comment on unique or additional depression characteristics such as symptom severity at the time of assessment. Of clinical relevance, some patients with MDD show
cognitive difficulties whereas others do not. The emphasis on
MDD collectively has left a gap in the research, and in turn clinical
practice, concerning the relationship between magnitude of depression severity and neurocognitive function (Zakzanis et al., 1999).
The result of this gap is significant, as cognitive impairments
associated with MDD can significantly reduce function, impair
quality of life, and contribute to disability (Jaeger, Berns, Uzelac,
& Davis-Conway, 2006; Naismith, Longley, Scott, & Hickie,
2007).
Major depression has been negatively associated with the neuropsychological domains of executive function (Harvey et al.,
2004), attention and concentration (Kampf-Sherf et al., 2004),
memory (Fossati, Amar, Raoux, Ergis, & Allilaire, 1999), and
processing speed (Nebes et al., 2000). In a meta-analysis of 22
studies, Zakzanis and colleagues (1999) showed that declarative or
Shawn M. McClintock, Department of Psychiatry, University of Texas
Southwestern Medical Center at Dallas and Department of Psychiatry,
Division of Brain Stimulation and Therapeutic Modulation, New York
State Psychiatric Institute, Columbia University; Mustafa M. Husain, Tracy
L. Greer, and C. Munro Cullum, Department of Psychiatry, University of
Texas Southwestern Medical Center at Dallas.
We acknowledge the careful review and helpful suggestions of Cheryl
H. Silver, Betsy Kennard, Carroll Hughes, and Judy Shaw.
Correspondence concerning this article should be addressed to Shawn
M. McClintock, Department of Psychiatry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390 –
8898. E-mail: shawn.mcclintock@utsouthwestern.edu
MDD
Depression has been found to be the fourth leading cause of
disability worldwide (Moussavi et al., 2007), and those with depression have a higher mortality rate relative to those persons not
(text continues on page 25)
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Table 1
Prior Research Investigations of Major Depressive Disorder (MDD), Depression Severity, and Neurocognitive Function
Year
Author
Sample
MDD (n ⫽ 13);
dysthymics (n ⫽ 17);
controls (n ⫽ 18)
1997 Paradiso, Lamberty,
Garvey, &
Robinson
History of MDD (n ⫽
20) or bipolar disorder
(n ⫽ 11) who were
currently euthymic,
and nonpatient group
(n ⫽ 19)
1998 Kessing et al.
Neurocognitive measures
Age range not reported, WCST, WAIS–R
but mean ages
ranged from 38.1
to 40.7 between
groups; participants
were not medicated
Clinical measures
DSM–III–R diagnoses
established by SCID–I;
depression severity
assessed with BDI and
21-item HAM–D
Age range not reported, TMT–A, TMT–B, CERAD DSM–III–R diagnoses
but mean ages
Word List Memory
established by SCID–I;
ranged from 49.8
Test, Stroop, and Digit
symptom severity
to 55.9 between
Symbol subtest of
assessed with 23-item
groups; medication
WAIS–R
HAM–D (score of 14 or
status varied, but
less required), Manic
most were on
Behavior Rating Scale
medications
(score of 16 or less
required)
MDD with three or more Age range: ⬎ 40;
CAMCOG, MDRS, GBS, Diagnosis established with
depressive episodes
patients were
GDS, MMSE
ICD–10 criteria;
(n ⫽ 68); MDD with
identified through
depression severity
one depressive episode
Danish psychiatric
assessed with 17-item
(n ⫽ 50); bipolar
case registry who
HAM–D and BDI
disorder with more
had received
than one episode (n ⫽
psychiatric
28) (all patient groups
hospitalization;
were in euthymic
controls had same
phase); controls
access to care;
(n ⫽ 58)
medication status
varied
Outcome
MDD group performed
significantly worse on
the Digit Span subtest
of the WAIS–R; no
group differences on
WCST; however, BDI
score significantly
predicted WCST Total
Errors, Perseverative
Responses, and Failure
to Maintain Set
MDD group performed
significantly worse than
controls on TMT–A,
TMT–B, Stroop, Digit
Symbol, and the
CERAD word list
memory test
On all cognitive measures,
patients with recurrent
depressive episodes were
significantly more
impaired than those with
one episode; number of
depressive episodes was
significantly associated
with cognitive decline as
measured by the
CAMCOG and MDRS;
patients with recurrent
depressive episodes were
significantly more
impaired on all measures
than controls
Characteristics of
depression severity
Symptom severity
scores indicated
depressed groups did
not significantly
differ from one
another, with mean
HAM–D scores
of 19.0 ⫾ 8.88 in
MDD group and
16.4 ⫾ 6.31 for
dysthymics (both
moderate range); BDI
scores were in
moderate range for
depressed group
(22.23 ⫾ 11.16) and
mild for dysthymic
(16.35 ⫾ 7.91);
control scored in
normal range
Inclusion criteria
required
hospitalization and/or
two or more MDEs
within a 2-year
period (i.e., all were
chronic)
Groups were compared
on the basis of
number of episodes
(one vs. three or
more)
(table continues)
MCCLINTOCK, HUSAIN, GREER, AND CULLUM
1991 Martin, Oren, &
Boon
Sample characteristics
Table 1 (continued)
Year
Author
Sample
Sample characteristics
Neurocognitive measures
Clinical measures
MDD inpatients (n ⫽
41); normal controls
(n ⫽ 20); MDD
patients treated with
pharmacotherapy,
psychotherapy or both
for 4.5 months and
retested (n ⫽ 27)
Age range: 31 to 68
years
RAVLT Versions A and
DSM–III–R diagnoses
B, WMS–R, Corsi
established by SCID–I;
Block Tapping Test,
symptom severity
Five-Point Test,
assessed with BDI, CSD,
COWAT, Block Design,
and MADRS
Go/No-Go
1999 Fossati, Amar,
Raoux, Ergis, &
Allilaire
MDD inpatients (n ⫽
20); schizophrenic
inpatients (n ⫽ 14);
normal controls
(n ⫽ 20)
Age range: 18 to 45
years
Verbal fluency, MCST,
Delis test; WAIS–Digit
Span Forward and
Backward and
Visuomotor Span
Forward and Backward,
Grober and Buschke’s
Verbal Learning Test
2000 Burt, Prudic,
Peyser, Clark, &
Sackeim
Young adult with MDD
(n ⫽ 29), older group
with MDD (n ⫽ 24),
young adult with
bipolar (n ⫽ 13) and
older group with
bipolar (n ⫽ 13)
Inpatient sample
SRT; paired-word and
referred for treatment
paired-face tasks;
with ECT; older
randomization to Rey–
group defined as 60
Osterrieth, Taylor, or
or greater; no
Richie Figure, Randt
medications except
Memory Test
lorazepam for 5 days
prior to testing;
psychotic symptoms
allowed
DSM–IV diagnoses
established by checklist;
symptom severity
assessed with MADRS
and SRRS (MDD
required scores of 20 or
more); schizophrenics
required score of 60 or
more on PANSS
Diagnoses established with
SADS; symptom severity
assessed with 24-item
HAM–D (score of 18 or
more required)
Characteristics of
depression severity
MDD group performed
Although all participants
significantly worse on
were inpatients, there
all tasks compared to
was a wide range of
controls at first
severity based on
examination; treated
symptom scores—
patients at follow-up
median MADRS
showed significant
was 16 (mild range),
improvements on visual
with a range
paired association test,
from 5 (no depression/
Block Design, Corsi
remission) to 43
Block-Tapping,
(severe-very severe
COWAT, design
range)
fluency, and reaction
times in the flexibility
task; responders showed
better improvements
than nonresponders
MDD and patients with
All were inpatients with
schizophrenia
moderate level of
significantly worse
severity required
compared to controls
at entry (mean
on: Digit Span Forward,
MADRS ⫽ 23.7
Visuospatial Backward,
⫾ 4.3)
semantic fluency, and
spontaneous and
structured sorting on the
Delis test; MDD
significantly worse
compared to controls on
Verbal Span Backward;
no correlation between
symptom severity
ratings and cognitive
performance
Older group with MDD
Although sample was
had poorer performance
inpatients referred for
on delayed reproduction
ECT, HAM–D score
of complex figures than
required for entry
young MDD or young
was at upper end of
bipolar; greater
mild range (18)
depression severity was
associated with greater
impairment on delayed
recognition memory
(table continues)
DEPRESSION SEVERITY AND NEUROCOGNITIVE FUNCTION
1999 Beblo, Baumann,
Bogerts,
Wallesch, &
Herrman
Outcome
11
12
Table 1 (continued)
Year
Author
Sample
One group of adults
recruited for aging
project (n ⫽ 50)
2000 Nebes et al.
Older group MDD (n ⫽
39); normal older
controls (n ⫽ 19)
2000 Sweeney, Kmiec, &
Kupfer
Inpatients with bipolar
(n ⫽ 35; 21 in
depressed state, 14 in
mixed or manic state)
or MDD (n ⫽ 58);
healthy controls
(n ⫽ 51)
Age range: 56 to 84
years
Neurocognitive measures
Clinical measures
Outcome
PASAT; TMT-B;
WAIS–R Digit Span
Depression severity assessed Significant positive
with BDI and GDS
correlations were found
between the TMT–B
and both depression
severity measures; total
BDI score accounted
for 18% of the variance
on TMT–B
Age range not reported, n back test; WAIS–R Digit DSM–IV diagnosis
Patients performed
but mean age was
Symbol Substitution
established by SCID–I;
significantly worse than
⬃70 or greater;
test; Block Design
depression severity
controls on working
participants were
subtest of WAIS–III,
assessed with 17-item
memory and processing
tested before and
Logical Memory subtest
HAM–D (required score
speed tasks; processing
after treatment with
of WMS–III, CVLT,
of 15 or more)
reductions appear to
either nortriptyline or
and CFT
mediate impairments on
paroxetine
episodic memory tasks;
baseline HAM–D and
age of onset of illness
did not affect results
Age range not reported, CANTAB
but mean ages
ranged from 31.9
to 36.31 between
groups
DSM–IV diagnosis
established by SCID–I;
symptom severity
assessed with 17-item
HAM–D, BPRS, BRMS,
SAPS
MDD performed
significantly worse on
measures of episodic
memory (Delayed
Matching to sample);
MDD reaction times
were relatively fast,
suggesting a
speed/accuracy tradeoff; severity of
depression and
psychosis severity
correlated with performance on many of the
tasks
Characteristics of
depression severity
Mean symptom severity
scores were not
reported, but were
used to correlate with
neuropsychological
performance
Inclusion required
HAM–D in moderate
range—mean
was 23.3 ⫾ 4.5; 20
participants were
recurrent, 19 were
experiencing first
episode; 15 were
early onset (before
age 59), 24 were late
onset (age 60 or
later)
All were inpatients, but
level of symptom
severity was varied—
mixed bipolar group
had mean HAM–D
score consistent with
mild depression
(12.93 ⫾ 9.09),
bipolar depressed
group was in
moderate range
(17.30 ⫾ 5.46), and
nonbipolar depressed
was in severe range
(21.64 ⫾ 4.30)
(table continues)
MCCLINTOCK, HUSAIN, GREER, AND CULLUM
2000 McBride & Abeles
Sample characteristics
Table 1 (continued)
Year
Author
Sample
Sample characteristics
Neurocognitive measures
Clinical measures
MDD (n ⫽ 123); healthy Nonbipolar, nonchronic TMT–A, Digit Span, CPT,
controls (n ⫽ 26)
outpatients; the mean
Hopkins Verbal
age of MDD group
Learning Test, WMS–
was 39.0 ⫾ 10.4,
R–Visual Reproduction
and mean age of the
Scale, Halstead–Reitan
healthy control group
Category Test,
was 40.2 ⫾ 9.7
COWAT, WCST,
TMT–B, CANTAB
DSM–IV diagnosis
established by SCID–I;
depression severity
assessed with 17-item
HAM–D (required score
of 15 or more)
2001 Kiosses, Klimstra,
Murphy, &
Alexopoulos
Older MDD (n ⫽ 126)
DSM–IV and RDC
diagnoses established
with SADS; symptom
severity assessed with
24-item HAM–D
Age range: 60 or
greater; both
outpatients and
inpatients;
medication status
was varied
DRS
Characteristics of
depression severity
MDD group performed
Moderate symptom
significantly worse than
severity required
healthy controls on
at entry (M ⫽
WCST (categories,
16.7 ⫾ 5.4); sample
perseverative responses
was nonchronic
and errors, and failure
(episode less than 2
to maintain set);
years duration);
clinician-rated
number of episodes
depression severity was
varied with 42 having
related to performance
single episode, 38
on two executive
having 1–2 episodes,
function tasks (ID/ED
and 43 having 3 or
task), motor skill and
more episodes; mean
reaction time from
age of onset was
CANTAB; patients who
27.9 ⫾ 12.5 years
did not improve
after 28 days of
treatment were more
impaired on the WCST
and the ID/ED task
from CANTAB; age of
onset of first episode
significantly negatively
correlated with
measures of attention,
psychomotor speed, and
executive function;
longer depressive
episodes were
associated with poorer
performance on WCST
failure to maintain set
Impairment on the
Severity was varied, with
initiation and
inclusion of both
perseveration subscale
outpatients and
was associated with
inpatients; mean
more functional
HAM–D was 27.29 ⫾
impairment and
5.88, but ranged
disability than severity
from 18 to 44 (mild to
of depression (using a
very severe)
HAM–D cut-off score
of 27)
(table continues)
DEPRESSION SEVERITY AND NEUROCOGNITIVE FUNCTION
2001 Grant, Thase, &
Sweeney
Outcome
13
14
Table 1 (continued)
Year
Author
Sample
Sample characteristics
Neurocognitive measures
Clinical measures
MDD (n ⫽ 22); healthy
controls (n ⫽ 30)
Age range not
specified, but mean
age was ⬃40 for
both groups; no
medications
(antidepressants,
lithium or
neuroleptics) for at
least 1 month prior
to testing
APT (Tasks a to d), APT
DSM–III–R diagnosis
Choice Reaction Time,
established by SCID–I;
difference between
depression severity
TMT–B and TMT–A,
assessed with BDI
Digit Symbol Test,
PASAT, Digit Span
Forward, Randt Memory
Test, Kimura Recurring
Recognition Figures
Test, COWAT, WAIS
Block Design
2001 Neu et al.
Inpatient group (n ⫽ 80)
comprised of MDD,
bipolar disorder,
dysthymia, and
schizoaffective
disorder, depressive
type; healthy controls
(n ⫽ 62); patients
tested at admission
and discharge
Age range: 30 to 60
years; medication
status varied—about
two thirds were
medicated and one
third was not at time
of admission
RAVLT Animal Naming,
WMS Visual Memory
subscale, TMT–A
DSM–IV diagnoses
established with clinical
interview; depression
severity assessed with
BRMS
Characteristics of
depression severity
MDD group scored
Majority (n ⫽ 16) of
significantly lower than
patients were
controls on selective
recurrent; mean BDI
attention, working
score was 23.0 ⫾ 6.7
memory, verbal long(moderate range);
term memory, and
controls scored in
verbal fluency; selective
normal range
attention and working
memory met criteria for
selective or differential
deficits in the MDD
group; BDI scores did
not correlate with
neuropsychological test
performance
Group with depression (all Group with depression
patient group)
had median of 3.0
performed significantly
episodes of illness
worse than controls on
and 2.0 inpatient
verbal memory,
hospitalizations;
psychomotor speed, and
mean age at onset of
verbal fluency at
MDD was 41.38 ⫾
admission; MDD group
12.96; mean BRMS
performed significantly
score was
worse on verbal
19.74 ⫾ 4.86
memory only at
admission and showed
significant
improvements on verbal
memory and verbal
fluency at discharge;
BRMS score was used
as covariate, but did not
influence any of the
results
(table continues)
MCCLINTOCK, HUSAIN, GREER, AND CULLUM
2001 Landro, Stiles, &
Sletvold
Outcome
Table 1 (continued)
Year
Author
Sample
Sample characteristics
Neurocognitive measures
Group with depression
Age range: 19 to 72
Free and cued selective
(n ⫽ 49) comprised of
years; inpatients;
reminding procedure,
both MDD (n ⫽ 36)
sample divided into 4
MCST
and bipolar disorder
subgroups with an
(n ⫽ 16); normal
age cut-off of 45
controls (n ⫽ 70)
years to assess the
effect of age on
memory performance
2002 Rohling, Green,
Allen, & Iverson
Patients with a variety
of health issues (n ⫽
420) who were
divided into two
groups based on BDI
score quartiles: low
depression group
(bottom quartile;
n ⫽ 115) and high
depression group
(highest quartile;
n ⫽ 112)
Age range not reported, WCST, Thurstone Word
but mean
Fluency Test, Ruff
age ⫽ 42.4;
Figural Fluency Test,
medication status not
Category Test; CVLT,
reported, but likely
RMT–W, CSRT; CFT,
varied based on
RMT–F; WAIS–R Digit
treatments for
Span, TMT; Finger
different medical
Tapping Test, Grip
diagnoses; patients
Strength, Grooved
who failed symptom
Pegboard, Finger Tip
validity tests were
Number Writing
excluded
DSM–IV diagnoses
established by checklist;
depression severity
assessed with MADRS
and SRRS (MDD
required scores of 20 or
more)
Outcome
Characteristics of
depression severity
Patients showed
All were inpatients with
significant impairments
at least moderate
compared to controls on
severity required at
free recall that was not
inclusion; mean
attributed to age effects;
MADRS score was
patients with mild
slightly greater
executive impairment
than 25 for both
based on the MCST had
older and younger
significantly lower
depressives,
recall scores that those
indicating moderate
with no executive
severity; older
impairment, which was
depressed had greater
again not associated
age at first episode
with age
(45.7 ⫾ 13.21)
compared to younger
(25.3 ⫾ 6.71), but
longer duration of
illness; groups were
similar with respect
to number of episode
and hospitalizations
Depression severity assessed No significant differences Low depression group
with BDI, MMPI–2
were noted between
had a mean BDI
(Depression Scale), and
high and low depressed
score consistent with
SCL-90-R (Depression
groups on effortful or
no depression; high
Scale)
automatic tasks; the
depressed group was
high depressive group
consistent with severe
performed significantly
depression; difference
worse on two tasks
between groups was
from the psychomotor
verified with MMPI–
and sensory-perceptual
2 and SCL–90–R
category: the Grooved
scores; groups
Pegboard and Finger
differed significantly
Tip Number Writing
on all three measures
(left hand)
(table continues)
DEPRESSION SEVERITY AND NEUROCOGNITIVE FUNCTION
2002 Fossati, Coyette,
Ergis, & Allilaire
Clinical measures
15
16
Table 1 (continued)
Year
Author
2002 Taylor, Wagner, &
Steffens
Sample
2003 Farrin, Hull, Unwin, Mildly depressed (n ⫽
Wykes, & David
43); nondepressed
(n ⫽ 59)
2003 Hammar, Lund, &
Hugdahl
MDD (n ⫽ 21) tested at
two time
points—inclusion and
6-month follow-up;
healthy controls
(n ⫽ 21)
Neurocognitive measures
Age range: 60 or
MMSE
greater; medication
status varied, but all
participants were in a
treatment program;
patients tested at
baseline, 6 months,
and 12 months
All male U.K. military
personnel; age range:
22 to 58 years
SART, PASAT, Stroop;
WMS–R Logical
Memory and Paired
Associates subtests
Age range: 20 to 56
years; patients
received
antidepressant
treatment; both
inpatients and
outpatients, but
majority were
inpatients (n ⫽ 18)
Visual search paradigm
examining automatic
and effortful processing
Clinical measures
Outcome
Characteristics of
depression severity
Depression severity assessed Both symptom severity
Inclusion required mild
with MADRS (score
and cognitive status
depression; mean
of 15 or greater required)
improved over time; a
MADRS score was in
higher baseline
moderate range
MADRS was associated
(30.3 ⫾ 8.7)
with a lower baseline
decreasing to mild
MMSE and less
range at 12 months
improvement in MMSE
(10.1 ⫾ 9.2)
over time
Mild depression defined as
Mildly depressed scored
Mean BDI ⫽ 18.19 ⫾
BDI score ⬎ 10;
significantly lower on
6.50, consistent with
nondepressed defined as
Logical Memory
mild range;
BDI ⬍ 10
immediate recall, made
nondepressed mean
significantly more errors
in normal range
of commission on the
SART, and had a
slower reaction time
following an error on
the SART
DSM–IV criteria met for
MDD significantly
All participants had
recurrent MDD;
differed from healthy
recurrent depression;
depression severity
controls on effortful
mean HAM–D ⫽
assessed with HAM–D
processing at both
21.9 ⫾ 3.7; did not
(required score of 18 or
testing sessions, despite
include information on
more)
improvements in
duration of illness, but
depressive severity
suggested that this
could have impacted
results
(table continues)
MCCLINTOCK, HUSAIN, GREER, AND CULLUM
Older patients with
depression (n ⫽ 52),
were diagnosed with
mild cognitive
impairment at baseline
Sample characteristics
Table 1 (continued)
Year
Author
Sample
Sample characteristics
Neurocognitive measures
Clinical measures
MDD (n ⫽ 27); healthy
controls (n ⫽ 23)
Age range: 26 to 59
years; mixture of
inpatients and
outpatients; all but
one patient was
taking at least one
antidepressant or
mood stabilizer
Probability Reversal task;
CANTAB Spatial
Working Memory task;
groups were divided
such that half received
negative feedback and
half did not
2003 Naismith et al.
MDD (n ⫽ 55); healthy
controls (n ⫽ 22)
Age range: 30 to 82
years (MDD), 40
to 74 years
(controls);
medication status
varied; both
inpatients and
outpatients included;
both nonpsychotic
and psychotic
features included; 12
participants
diagnosed with
bipolar disorder
TMT–B, RAVLT, Raven’s DSM–IV diagnoses
Colored Progressive
established with SCID–I;
Matrices, WAIS–R
depression severity
Block Deign and
assessed with 21-item
Vocabulary subtests,
HAM–D
Benton Visual Retention
Test (Form D,
Administration A),
Phonetic and Semantic
Fluency, computerized
WCST, simple and
choice reaction time,
computerized version of
the Tower of London
DSM–IV diagnoses
established with clinical
interview; depression
severity assessed with
HAM–D, MADRS, CID;
control participants
assessed with BDI (score
or 9 or less required)
Characteristics of
depression severity
Patients had significantly Symptom severity was in
worse performance on
moderate to severe
maintenance failure
range—mean HAM–D
and matching on the
score was 23.6 ⫾
Probability Reversal
4.2, MADRS was
task and between34.3 ⫾ 5.4
search errors on the
Spatial Working
Memory task; feedback
improved performance
in both MDD and
controls; no
relationship between
symptom severity
scores and
neuropsychological test
performance
MDD patients performed
Mean HAM–D was in
significantly worse on all
severe range; average
tests except WAIS–R
duration of illness
Vocabulary and WCST;
was 45 weeks
higher HAM–D scores
were significantly
associated with lower z
scores on semantic
fluency and WCST
(perseverations); no
association between
length of episode or
lifetime diagnoses and
neuropsychological test
performance; inpatients
were significantly worse
on RAVLT percentage
retention; later age of
onset (ⱖ50 years)
performed worse than
early onset on WAIS–R
Block Design, CPT,
TMT–B, Tower of
London, and Raven’s
Matrices, although only
Tower of London
remained significant
when age was added as a
covariate
(table continues)
DEPRESSION SEVERITY AND NEUROCOGNITIVE FUNCTION
2003 F. C. Murphy,
Michael,
Robbins, &
Sahakian
Outcome
17
18
Table 1 (continued)
Year
Author
2003 Porter, Gallagher,
Thompson, &
Young
Sample
MDD (n ⫽ 44); healthy
controls (n ⫽ 44)
Neurocognitive measures
Clinical measures
Age range: 18 to 65
Digit Symbol Substitution
years; free of all
Test; RAVLT;
psychotropic
Visuospatial CANTAB
medications at least 6
Paired-Associates
weeks prior to
Learning, Pattern
recruitment
Recognition, Spatial
Recognition and
Simultaneous/Delayed
Matching to Sample
subtests; COWAT,
ELFT, Vigil CPT, and
CANTAB Spatial
Working Memory and
Tower of London
subtests
DSM–IV criteria were met;
depression severity
assessed with 17-item
HAM–D, MADRS, BDI
Age range: 20 to 64
years; 47 participants
across the four
depressed groups
were treated with
psychotropic
medications
DSM–IV diagnoses
established by SCAN
Episodic memory task
consisting of 32 words
in eight categories;
Word Association Test,
TMT–A, TMT–B
Outcome
Characteristics of
depression severity
MDD performed
Most were first episode
significantly worse than
(n ⫽ 30); mean
controls on the RAVLT
symptom severity
(list-learning and
scores were in the
distractor list); all
moderate range, but
CANTAB visuospatial
range was—mean
tasks; all sustained
HAM–D ⫽ 21.1 ⫾ 4.4
attention and executive
(range 15 to 30),
function tasks except
MADRS ⫽ 28.9 ⫾ 5.5
the Tower of London
(range 18 to 38);
task; HAM–D scores
BDI ⫽ 27.9 ⫾ 10.2
were significantly
(range 8 to 47)
correlated with performance on RAVLT
(retroactive interference,
long-term recall, and
retroactive interference),
pattern recognition
(percentage correct),
Delayed Matching to
Sample and PairedAssociates Learning
(total trials); illness
characteristics were
provided but were not
related to
neuropsychological test
performance
MDD group recalled
Severity was based on
fewer words on free
categorical
and cued recall
psychiatric diagnosis;
compared to controls;
Symptom severity at
mixed anxietytime of testing was
depressive disorder
not assessed
group recalled fewer
cued recall words than
controls; combined
depressed group (i.e.,
all four subgroups) had
a longer TMT–B
completion time
compared to controls,
only the dysthymic
subgroup independently
differed from controls
on the TMT–B
(table continues)
MCCLINTOCK, HUSAIN, GREER, AND CULLUM
2004 Airaksinen, Larsson, MDD (n ⫽ 68);
Lundberg, &
dysthymia (n ⫽ 28);
Forsell
mixed anxietydepressive disorder
(n ⫽ 25); minor
depression (n ⫽ 66);
controls (n ⫽ 175)
Sample characteristics
Table 1 (continued)
Year
Author
Sample
Sample characteristics
Older MDD (n ⫽ 21);
normal control
(n ⫽ 19)
MDD age range: 53
to 93 years; control
age range: 61 to 85
years; no
medications, no
psychotic features
2004 Biringer et al.
Recurrent MDD (n ⫽
50) tested before and
after (n ⫽ 30) a 26month test–retest
interval
Age range: 20 to 50
years; majority on
psychotropic
medication
Clinical measures
Outcome
COWAT, CET, Hayling
DSM–IV diagnosis
MDD group performed
Test, SCIT, TMT–A,
established by clinical
significantly worse than
TMT–B, Graphic
interview, MADRS, GDS,
controls on Logical
Sequences of Luria,
and ERD; must have
Memory I and all
MCST, Logical Memory
MADRS ⬎ 20
executive function
I, Digit Span Forward,
measures except
Corsi Block Tapping
Hayling Test; severity
Test
(MADRS) was
significantly correlated
with performance on
many executive
function measures
(COWAT, MCST,
TMT–B [time], Hayling
test [Section B])
WCST (categories
DSM–IV diagnoses
HAM–D change scores
completed, perseverative
established with MINI;
(reverse scaled) were
errors, failure to
depression severity
significantly positively
maintain set,
assessed with 17-item
correlated with a
nonperseverative errors),
HAM–D and MADRS
composite change score
PASAT (2- and 3-s
(minimum scores of 18
of executive function
subtests), WAIS–R–
on both)
based on all measures;
Backward Digit Span,
the only significant
Stroop, COWAT
correlation on
(phonemic and semantic
individual tasks was
categories)
between HAM–D and
COWAT (number of
words in semantic
categories); recovered
patients (HAM–D ⬍ 8,
i.e., remitted) showed
greater mean
improvements on 8 of
the 10 measurements
than nonrecovered
patients; course of
illness characteristics
were not related to
neuropsychological test
performance
Characteristics of
depression severity
Moderate level of
severity required for
entry; group with
depression had mean
MADRS of 33.3 ⫾
6.3, which falls in the
moderate severity
range; control group
scores consistent with
no depression
Mean HAM–D in
severe range; all had
long duration of
disease, but those
who did retest
differed significantly
from those who did
not (mean years
13.6 ⫾ 9.3 vs. 6.1 ⫾
5.1, respectively)
DEPRESSION SEVERITY AND NEUROCOGNITIVE FUNCTION
2004 Baudic, Tzortzis,
Barba, &
Traykov
Neurocognitive measures
(table continues)
19
20
Table 1 (continued)
Year
Author
Sample
Sample characteristics
Neurocognitive measures
Clinical measures
MDD inpatients (n ⫽
22); healthy controls
(n ⫽ 22)
Age range: 22 to 53
years; medication
status varied, but
most were on
tricyclic
antidepressants
2004 Kampf-Sherf et al.
MDD (n ⫽ 55)
Age range not reported; TMT–A, TMT–B, Purdue
participants were
Pegboard, CFT,
tested at baseline and
RAVLT, BVRT,
again following 6
WAIS–R Arithmetic,
weeks of SSRI
Block Design and
treatment
Similarities subtests,
HVOT, modified verbal
fluency measure, VFOT
DSM–IV diagnosis of MDD
established with SCID–I;
depression severity
assessed with HAM–D
2004 Leuchter et al.
MDD (n ⫽ 51); NP
testing occurred at
baseline and was
included to determine
whether it might
predict participants
who were likely to
respond to placebo
Age range: ⬎ 21;
treatment with either
fluoxetine,
venlafaxine, or
placebo ⫹15 to 20
min of brief
supportive
psychotherapy
DSM–IV diagnosis of MDD
established with SCID–I;
depression severity
assessed with 17-item
HAM–D (required
score ⱖ 16)
Verbal n-back task; load
DSM–IV diagnoses
and mental manipulation
established with MINI;
within working memory
depression severity
assessed with three
assessed with MADRS
different levels of
(score of 20 or higher
complexity;
required) and BDI
WAIS–Digit Span
Forward and Backward
and Visuospatial Span
Forward and Backward,
TMT–A, TMT–B,
MCST, Stroop, word
fluency
TMT–A, Stroop A and B,
Digit Symbol Test,
TMT–B, WCST,
Auditory Consonant
Trigrams, COWAT,
Stoop Trail, Language:
Boston Naming Test,
verbal learning:
RAVLT, WMS–R
Visual Reproduction,
CFT Figure, Digit Span,
WAIS–R Block Design,
CFT Copy, Benton
Facial Recognition
Characteristics of
depression severity
MDD group scored
Moderate level of
significantly lower than
severity was required;
controls on all
mean MADRS score
complexity levels of the
was in the moderate
n-back test, the TMT–B
range (27.7 ⫾ 4.3);
test, number of
mean years of illness
perseverative errors on
was 8.2 ⫾ 11.3
the WCST, number and
years; mean number
speed of response on
of depressive
the Stroop (color and
episodes was 2.8 ⫾
interference); those with
2.4; mean number of
multiple hospitalizations
hospitalizations for
performed lower on
depression was
n-back test compared to
1.9 ⫾ 1.2
those hospitalized for
the first time
SSRI responders
Symptom severity
performed more poorly
scores on HAM–D
than nonresponders on
not reported, but
more complex tasks
were rank ordered by
WAIS–R subtests,
responsiveness
HVOT, BVRT correct
(difference between
responses and
scores before and
perseverations, and CFT
after treatment); those
strategy and performed
with difference scores
better than
of 9 and above were
nonresponders on verbal
classified as
fluency and VFOT
responders
Placebo responders
Baseline HAM–D was
performed significantly
in severe range for
faster on the Digit
all groups
Symbol Test than
placebo nonresponders,
medication responders,
and medication
nonresponders
(table continues)
MCCLINTOCK, HUSAIN, GREER, AND CULLUM
2004 Harvey et al.
Outcome
Table 1 (continued)
Year
Author
Sample
Sample characteristics
Neurocognitive measures
Clinical measures
MDD or bipolar disorder Age range: 18 to 69
inpatients in depressive
years; all but four
episode (n ⫽ 73) tested
were receiving
before and after
pharmacological
admission to hospital
treatment at time of
(mean time ⫽
first testing; 10 had
12 weeks); recovered
psychotic features
(n ⫽ 19) retested 6
months later
German assessments of
alertness, divided
attention, two selective
attention tasks, German
equivalents of the TMT
and Stroop tests, verbal
and short-term memory:
WMS–R Digit Span
Forward and Backward,
computerized version of
WCST
DSM–IV diagnoses
established with clinical
interview; depression
severity assessed with
21-item HAM–D,
MADRS, BDI
2004 Stordal et al.
Recurrent MDD (n ⫽
45); healthy controls
(n ⫽ 50)
Age range: 19 to 51
years; mix of
inpatients and
outpatients;
medication status
varied
COWAT, Tower of
London, PASAT,
WAIS–R Digits
Backward, Stoop,
WCST; simple reaction
time from the California
Computerized
Assessment Package
DSM–IV diagnoses
established with SCID–I;
depression severity
assessed with 17-item
HAM–D (score of 18 or
greater required) and
MADRS
2005 Alexopoulos et al.
Nondemented older
patients with MDD
(n ⫽ 112)
Age ⬎ 60 years; MDD of MDRS–IP, Stroop
moderate severity
(HAM–D score
24.33 ⫾ 4.70); all
participants treated
with 40 mg citalopram
for 8 weeks; NP testing
was used to predict
response to citalopram
DSM–IV diagnoses
established with the
SADS and parts of the
SCID–I, patient version;
depression severity
assessed with 24-item
HAM–D
Characteristics of
depression severity
36 participants had
Patients were impaired on
single episode, 32
all cognitive tests at
admission except Digit
recurrent; wide range
Span Forward and
of symptom severity,
Stroop; impairments
with means in the
remained at discharge
moderate to severe
with the exception of
range—HAM–D ⫽
performance on the letter
29.27 ⫾ 6.97,
cancellation task
MADRS ⫽ 33.52 ⫾
assessing selective
7.44, BDI ⫽
attention; nonresponders
25.7 ⫾ 10.27
and nonremitters
performed significantly
worse on the divided
attention task at
admission; significant
positive correlations
between lifetime duration
of illness and reaction
time on alertness and
divided attention tasks;
divided attention was
significantly associated
with course of disorder
MDD patients performed
All participants were
significantly worse
recurrent with two to
compared to controls on
five MDEs; both
the COWAT (phonemic
inpatients and
and categorical verbal
outpatients who were
fluency), Stroop (Colormoderate to severely
Word subtest), WCST
depressed—mean
(failure to maintain set
HAM–D ⫽ 28.80 ⫾
and perseverative errors),
4.39, MADRS ⫽
PASAT, and Digits
22.41 ⫾ 4.42
Backward; psychomotor
speed accounted for
approximately one fourth
of the observed
impairments
Citalopram nonresponders Inclusion criteria
performed significantly
required moderate
worse on the MDRS–IP
symptom severity;
subscale and the Stroop;
response defined
however, they were
as ⱖ 50% change in
older, less educated,
HAM–D score
and had a greater
medical burden
21
(table continues)
DEPRESSION SEVERITY AND NEUROCOGNITIVE FUNCTION
2004 Majer et al.
Outcome
22
Table 1 (continued)
Year
Author
2005 Rapp et al.
Sample
Sample characteristics
Older MDD (n ⫽ 116);
Age range: 60 to 97
two-by-two factorial
design—one factor
was current MDE
(present vs. absent),
the other was recurrent
MDD (present vs.
absent)
Age ⱖ 60
Clinical measures
TMT–A, TMT–B, Digit
Symbol Substitution
Test, Verbal Fluency,
task comprised of listlearning, recognition
and delayed recall
DSM–III–R or DSM–IV
diagnosis of MDD
established with
questionnaire; depression
severity assessed with
GDS
CVLT; WCST,
Letter–Number Sequences
from WAIS–III, Stroop
(Part 1)
DSM–IV diagnosis of MDD
established with SCID–I
and HAM–D ⬎ 15;
minor depression defined
as presence of low mood
and/or interest and one
additional depressive
symptom from DSM–IV
checklist and HAM–D
between 8–16
Outcome
Characteristics of
depression severity
MDD with current MDE
Late onset was defined
performed significantly
as no previous
worse than those not
history of MDD;
with current MDE on
recurrent was defined
attention/executive
as at least one prior
function tasks; patients
MDE; current
with late-onset MDD
symptoms on GDS
worse than all other
were significantly
groups on attention/
different for those in
executive function
versus out of current
tasks; patients with
MDE, irrespective of
recurrent MDD
chronicity
performed worse on
episodic memory tasks
than those with lateonset MDD
Major and minor older
Mean HAM–D scores
participants with
were 10.8 ⫾ 2.0
depression recalled
(mild range) for
significantly fewer
minor depression,
words on Trial 1 of List
17.4 ⫾ 4.4 (moderate
A and on List B and
range) for MDD
were more impaired on
semantic and serial
clustering compared to
controls; mediation
analyses conducted with
the other tasks showed
that performance
differences on Trial 5
are secondary to
executive dysfunction;
while both early and
late onset participants’
depression diagnosis
mediated CVLT
semantic clustering and
WCST performance;
effects were stronger in
late onset participants
(table continues)
MCCLINTOCK, HUSAIN, GREER, AND CULLUM
2006 Elderkin-Thompson, MDD (n ⫽ 63); minor
Mintz, Haroon,
depression (n ⫽ 32);
Lavretsky, &
healthy controls
Kumar
(n ⫽ 71)
Neurocognitive measures
Table 1 (continued)
Year
Author
Sample
Sample characteristics
Neurocognitive measures
Outcome
MDD performed
significantly worse than
normal controls on
Stroop errors, number
correct on shifting
attention test, and
reaction time on the
continuous performance
test; MDD performed
significantly worse than
treated MDD on
complex attention and
vigilance tasks; treated
MDD did not differ
significantly from
controls on pairwise
comparisons, but
summary scores
indicated that treated
MDD performed worse
on four of six domains
and 10 of 15 primary
scores, suggesting that
treatment did not
normalize performance
No significant performance differences were
found
2006 Gualtieri, Johnson,
& Benedict
MDD on no
psychotropic
medications (n ⫽ 38);
MDD on psychotropic
medications who had
been successfully
treated for at least 4
weeks (n ⫽ 31);
normal controls
(n ⫽ 69)
Age range: 18 to 65
years
CNS Vital Signs
computerized battery
DSM–IV diagnosis of MDD
established with clinical
interview; depression
severity assessed with
HAM–D and BDI
2006 Wang et al.
MDD currently
depressed (n ⫽ 57);
MDD previously
depressed (n ⫽ 42);
healthy controls never
depressed (n ⫽ 46)
Mean ages ranged
from 26.9 to 31.0
between groups;
medication status
varied, but majority
were not medicated
CVLT
DSM–IV criteria were met;
depression severity
assessed with BDI
Characteristics of
depression severity
Mean BDI ⫽ 16.86,
HAM–D ⫽ 15 in
untreated MDD
group; treated group
had mean scores in
the remitted range
(mean BDI ⫽ 1.5,
HAM–D ⫽ 6)
Mean BDI scores were
in mild to moderate
range for currently
depressed (15.8 ⫾
8.6) and normal
range for previously
and never depressed
(6.4 ⫾ 4.0 versus
1.1 ⫾ 1.7,
respectively)
(table continues)
DEPRESSION SEVERITY AND NEUROCOGNITIVE FUNCTION
Clinical measures
23
24
Table 1 (continued)
Year
Author
2007 Cysique et al.
Sample
Neurocognitive measures
Clinical measures
Age range not reported;
mean age ⫽ 32.1;
participants were
grouped into two
groups: those with a
history of MDD (trait
positive) and those
without (trait
negative); also
grouped based on
whether criteria for
MDE were met at
follow-up (state
positive and state
negative)
Subtests from WAIS–R
and Halstead–Reitan
Battery, PASAT, Figure
Memory Test, Story
Memory Test, Boston
Naming Test, Thurstone
Word Fluency Test,
motor skills: Finger
Tapping, Grooved
Pegboard
DSM–III–R diagnoses
established with the
SCID–I; depression
severity assessed with the
BDI and HAM–D
Outcome
Characteristics of
depression severity
Neither trait nor state
Participants did not
groups significantly
meet criteria for
differed on
MDD and mean
neuropsychological test
symptom severity
performance; however,
scores were within
state-positive
normal range at
participants at follow-up
baseline; statewere more likely to
positive participants
report subjective
had significant
neurocognitive
increases in symptom
complaints at both
severity scores at
baseline and follow-up
follow-up
Note. WCST ⫽ Wisconsin Card Sorting Test; WAIS–R ⫽ Wechsler Adult Intelligence Scale–Revised; DSM ⫽ Diagnostic and Statistical Manual of Mental Disorders; SCID–I ⫽ Structured Clinical
Interview for DSM–IV; BDI ⫽ Beck Depression Inventory; HAM–D ⫽ Hamilton Rating Scale for Depression; TMT–A ⫽ Trail Making Test–Part A; TMT–B ⫽ TMT–Part B; CERAD ⫽ Consortium
to Establish a Registry for Alzheimer’s Disease; Stroop ⫽ Stroop Color and Word Test; CAMCOG ⫽ Cambridge Cognitive Examination total score; MDRS ⫽ Mattis Dementia Rating Scale; GBS ⫽
Gottfries-Brane-Steen Dementia Rating Scale; GDS ⫽ Geriatric Depression Scale; MMSE ⫽ Mini-Mental State Examination; ICD–10 ⫽ International Classification of Diseases-10; RAVLT ⫽ Rey
Auditory Verbal Learning Test; WMS–R ⫽ Wechsler Memory Test–Revised; COWAT ⫽ Controlled Oral Word Association Test; CSD ⫽ Cornell Depression Scale; MADRS ⫽ Montgomery and
Asberg Depression Rating Scale; MCST ⫽ Modified Card Sorting Test; SRRS ⫽ Salpétrière Retardation Rating Scale; PANSS ⫽ Positive and Negative Symptom Scale; SRT ⫽ Buschke Selective
Reminding; SADS ⫽ Schedule for Affective Disorders and Schizophrenia; ECT ⫽ electroconvulsive therapy; WAIS–III ⫽ WAIS–3rd edition; PASAT ⫽ Paced Auditory Serial Addition Test; CVLT ⫽
California Verbal Learning Test; CFT ⫽ Rey–Osterrieth Complex Figure Test; CANTAB ⫽ Cambridge Neuropsychological Test Automated Battery; BPRS ⫽ Brief Psychiatric Rating Scale; BRMS ⫽
Bech–Rafaelsen Melancholia Scale; SAPS ⫽ Scale for the Assessment of Positive Symptoms; CPT ⫽ Continuous Performance Test; ID/ED ⫽ Intra-dimensional/Extra-dimensional; DRS ⫽ Dementia
Rating Scale; RDC ⫽ Research Diagnostic Criteria; APT ⫽ Automated Psychological Test; RMT–W ⫽ Warrington’s Recognition Memory Test–Words; RMT–F ⫽ RMT–Faces; CSRT ⫽ CogniSyst
Story Recall Test; MMPI–2 ⫽ Minnesota Multiphasic Personality Inventory–2; SCL–90 –R ⫽ Symptom Checklist–90 –Revised; SART ⫽ Sustained Attention to Response Task; CID ⫽ Clinical
Interview for Depression; ELFT ⫽ Exclude Letter Fluency Test; SCAN ⫽ Schedules for Clinical Assessment in Neuropsychiatry; CET ⫽ Cognitive Estimates Test; SCIT ⫽ Stroop Color Interference
Test; ERD ⫽ Scale for the Evaluation of Psychomotor Retardation in Depressed Patients; MINI ⫽ Mini International Neuropsychiatric Interview; SSRI ⫽ selective serotonin reuptake inhibitor; BVRT ⫽
Benton Visual Retention Test; HVOT ⫽ Hooper Visual Organization Test; VFOT ⫽ Visual Frequency of Occurrence Test; MDRS–IP ⫽ Mattis Dementia Rating Scale Initiation-Perseveration subtest;
MDE ⫽ major depressive episode; CNS ⫽ CNS vital signs.
MCCLINTOCK, HUSAIN, GREER, AND CULLUM
HIV-infected adult men
who did not meet
criteria for serious
mental illness or
current major
depressive episode at
baseline (n ⫽ 227)
Sample characteristics
DEPRESSION SEVERITY AND NEUROCOGNITIVE FUNCTION
depressed (Cuijpers & Smit, 2002). The lifetime prevalence of
MDD ranges between 5% and 20% (Hamet & Tremblay, 2005;
Kessler et al., 2003). The annual incidence of MDD has been
found to be three to five adults per 1,000 (J. M. Murphy, Laird,
Monson, Sobol, & Leighton, 2000) and it has been estimated that
5% to 25% of the population will experience depression at some
point in their lifetime (Kessler et al., 2003). Women are consistently diagnosed with MDD more frequently than men at a ratio of
2:1 (Kessler, 2003; Marcus et al., 2005), and younger cohorts (50
years and younger) have been found to have higher rates of
depression relative to older (51 years and older) cohorts (Husain et
al., 2005).
Defining Depression Severity
Severity of depression, and its potential effects on cognitive
function, should be considered both with respect to the level of
symptom severity at the time of neuropsychological testing (i.e.,
state of depressive symptomatology), and with respect to course of
illness (i.e., number and duration of depressive episodes, duration
of illness, treatment resistance). These different aspects of severity
may influence both neuropsychological performance and the potential resolution of cognitive impairments with treatment.
Evaluation of depressive symptoms at a particular time point is
typically done with symptom rating scales, such as the Hamilton
Rating Scale for Depression (HAM–D; Hamilton, 1960), or the
Inventory of Depressive Symptomatology (IDS; Rush, Gullion,
Basco, Jarrett, & Trivedi, 1996). Different total scores correspond
to various levels of severity. For example, scores ranging between 0 and 11 on the 30-item IDS and 0 to 7 on the 17-item
HAM–D represent no depression (or remission), whereas 47 or
greater on the IDS and 26 or greater on the HAM–D represent very
severe depression (http://www.ids-qids.org). These symptom severity scores are often correlated with neuropsychological test
performance to evaluate the relationship between symptom severity and cognitive function.
The presence or absence of psychotic features is also evaluated
when examining depression severity at the symptom level (Fennig,
Craig, Lavelle, Kovasznay, & Bromet, 1994). Psychosis, per the
Diagnostic and Statistical Manual of Mental Disorders (4th ed.,
text rev.; DSM–IV–TR; American Psychiatric Association, 2000),
is an indicator of depression severity rather than a subtype of
depression, and is qualified as either mood congruent (e.g., content
is consistent with depressive theme) or mood incongruent. Research has suggested that persons diagnosed with psychotic depression are older, have worse premorbid functioning and longer
depressive episode duration, and are more prone to future psychotic depressive episodes (Bromet et al., 1992; Craig, Grossman,
Bromet, Fochtmann, & Carlson, 2007; Naz et al., 2007).
In addition, aspects about individuals’ course of illness—such as
number of depressive episodes and duration of episodes, as well as
age at onset of depression—may impact cognitive performance.
Treatment resistance is also a relevant consideration, as it contributes to longer episodes, as well as the likelihood for exposure to
more types of psychotropic medications and combinations of psychotropic medications for a longer period of time, which is negatively associated with cognitive function (Gibel & Ritsner, 2008;
Neumann et al., 2002).
25
Of note, many studies included both inpatients and outpatients,
which contributes to a wide range of severity in study samples
being assessed. These patient samples (inpatients or outpatients)
are likely to differ on all aspects of severity discussed above. In
addition, they are likely to differ with respect to current treatments,
as well as past treatment history, both of which may be associated
with cognitive performance. Therefore, it is important to consider
the distribution of such patients in studies examining cognitive
impairment in depression.
Recurrent and Single Episode Depression
For those persons diagnosed with MDD, between 50% and 75%
experience more than one depressive episode (Gold & Chrousos,
2002; Harkness, Monroe, Simons, & Thase, 1999; Kennedy &
Paykel, 2004). Typically, the subsequent depressive episode occurs within 6 months after recovering from the first episode, with
recurrence increasing proportionally to the number of subsequent
episodes (Angst, 1999). Illustrating the high recurrence rate, a
longitudinal study following 69 participants with MDD over a
20-year time period showed that over 92% recovered on average
by 12 months (median recovery time was 7 months) and 67% of
those who recovered later had a recurrence of depression
(Kennedy, Abbott, & Paykel, 2003).
Recurrent depression has been suggested to be more severe and
disabling than single episode depression (Paradis, Reinherz, Giaconia, & Fitzmaurice, 2006). Those with chronic, recurrent depression have been shown to have more Axis I (i.e., anxiety, substance
abuse), Axis II (i.e., personality disorder), and Axis III (i.e.,
somatic complaints, somatic diseases) comorbidities (Katon, 2003;
Vuorilehto, Melartin, & Isometsa, 2005). Moreover, recurrent depression has been associated with increased negative perceptions
of social stimuli (i.e., vocal expressions, facial expressions) and
self (Bos et al., 2005), as well as poor marital and interpersonal
relationships and poor employment functioning (Elinson, Houck,
Marcus, & Pincus, 2004; Judd et al., 2000; Kennedy & Paykel,
2004; Kessler, 1997; Wilhelm, Parker, Dewhurst-Savellis, &
Asghari, 1999), which suggests recurrent depression, relative to
single episode, may be more deleterious. However, in The Netherlands Mental Health Survey and Incidence Study (Kruijshaar,
Hoeymans, Bijl, Spijker, & Essink-Bot, 2003), the severity of the
depressive episode was found to be more related to increasing
levels of disability as opposed to the number of depressive episodes. Thus, there is conflicting evidence as to whether severity of
the depressive episode or the number of depressive episodes may
contribute more strongly to the level of functional impairment.
Physiological correlates of recurrent MDD have included increased cortisol (Bos et al., 2005), glucocorticoids (Lampe et al.,
2003), and decreased hippocampal volume (Neumeister et al.,
2005). The reduction in the hippocampus was found to be most
prominent in the posterior region that has specific implications in
spatial learning and memory (Porter, Gallagher, Thompson, &
Young, 2003). A relationship has been shown to exist between
recurrent MDD and increased cortisol and decreased hippocampal
volume, as well as reduced cerebral gray matter volume (i.e.,
decrease in neuron and glial cell density and size; Cotter, Mackay,
Landau, Kerwin, & Everall, 2001; Rajkowska, 2000).
There is conflicting information regarding the association between cognitive function and recurrent depression. A major de-
26
MCCLINTOCK, HUSAIN, GREER, AND CULLUM
pressive episode (MDE) can be conceptualized as a traumatic
event that potentially could harm the brain and negatively impact
cognitive functioning, with more MDEs causing more harm than
one (Altshuler, 1993; Fossati, Coyette, Ergis, & Allilaire, 2002;
Rapp et al., 2005). Various researchers (Burt, Prudic, Peyser,
Clark, & Sackeim, 2000; Grant, Thase, & Sweeney, 2001) have
speculated that there is a cumulative, neurotoxic effect of MDEs
on brain physiology, which may be associated with neuropsychological dysfunction. For example, the number of depressive episodes has been associated with a decrease in cognitive performance (Kessing, 1998) on the Cambridge Cognitive Examination
total score (CAMCOG; Huppert, Brayne, Gill, Paykel, & Beardsall, 1995), a computerized neuropsychological screening tool.
Also, those with recurrent depression were found to be more
impaired on the Wisconsin Card Sorting Test (Heaton et al., 1993),
a measure of problem solving, the Paced Auditory Serial Addition
Test (Gronwall, 1977), a measure of attention and working memory, and the Stroop test (Stroop, 1935), a measure of inhibition and
executive function, compared to control participants (Stordal et al.,
2004).
In contrast, research by Grant et al. (2001) showed no relationship between the number of MDEs and performance on the Cambridge Neuropsychological Test Automated Battery (CANTAB;
Fray, Robbins, & Sahakian, 1996), a computerized screening battery that assesses memory, attention, and executive function. The
conflicting information regarding the association between the
number of MDEs and neurocognitive performance could be attributable to multiple factors including methodological (i.e., different
neurocognitive instruments) or sample (i.e., sociodemographic or
clinical characteristics) related differences among studies. Also,
although the number of MDEs may have a cumulative effect on
cognitive function, several investigators suggested that after the
depressive episode remits, cognitive functioning often returns to
normal. During the euthymic state, it is believed that the brain
heals itself, in turn improving and returning cognitive functioning
back to normal (Hammar, Lund, & Hugdahl, 2003; Neu et al.,
2005). However, other recent studies have suggested that at least
certain aspects of neurocognitive dysfunction (e.g., effortful attention) are resistant to antidepressant treatment (e.g., selective serotonin reuptake inhibitors, serotonin–norepinephrine reuptake inhibitor) and remain even when the depressive episode has remitted
(Gualtieri, Johnson, & Benedict, 2006; Paelecke-Habermann,
Pohl, & Leblow, 2005).
Neurophysiological and Neurobiological
Correlates of MDD
In general, MDD has often been associated with neurophysiological changes (Liotti & Mayberg, 2001). Studies using positron
emission tomography (PET) have shown decreased regional cerebral blood flow (rCBF) in areas that have been implicated in
affective disorders including the medial prefrontal cortex, anterior
cingulate, and the orbital frontal cortex (Dolan, Bench, Brown,
Scott, & Frackowiak, 1994; Elderkin-Thompson, Boone, Hwang,
& Kumar, 2004). Moreover, in a study of 10 depressed patients
assessing mood-congruent processing biases using functional magnetic resonance imaging (fMRI), it was found that abnormal responses were associated with the medial and orbital prefrontal
cortices (Elliott et al., 2002). Other neuroimaging studies have
shown abnormal functioning in frontal and limbic connections
using fMRI (Krishnan, Hays, & Blazer, 1997), or increased glucose metabolism in the caudate nucleus (Drevets, 2000), and the
limbic regions (Alexopoulos et al., 2005) using PET. In the study
by Krishan et al. (1997), late-life depression was hypothesized to
be related to vascular lesions in the frontal and limbic connections
that may dysregulate norepinephrine and serotonin circuitry. This
concept of “vascular depression” was proposed by Alexopoulos et
al. (1997), based on their finding of associations between depression, vascular lesions, and vascular risk factors. Additional research has found that cerebral emboli were greatly associated with
depressive symptoms, even after adjusting for demographic factors
in a cohort of older patients with vascular dementia (Purandare et
al., 2006). Though no investigations have examined the association
between vascular lesions and depression severity, this line of
investigation could provide useful information particularly with
regard to addressing the effects of the number of lesions and
depression severity, and then followed by treatment options (for a
comprehensive review, see Blazer, 2009).
Neurobiologically, serotonergic and hypothalamic pituitary axis
(HPA) dysfunction has been suggested to impact neurocognitive
functioning in those persons with depression (McAllister-Williams, Ferrier, & Young, 1998). As identified in PET studies, the
serotonergic system is abnormal in depressed patients as there are
fewer serotonin receptors (i.e., 5-HT1a) and the serotonin transportation mechanism (5-HTT) is inefficient (Drevets, Frank, &
Price, 1999). The above information helps to support the association between MDD, neuroanatomical regions, and neuropsychological processes; however, the nature of that relationship and the
potential impact of other factors is unclear.
Pseudodementia
Depression, when very severe, has been reported to cause such
significant cognitive impairments in some individuals such that
persons may be described as having pseudodementia, which is
defined as reversible impairment of memory secondary to depression (Salzman & Guitfreund, 1986). Although it may be difficult in
rare cases to differentiate dementia from pseudodementia, in true
dementia, cognitive decline progresses over time, whereas in
pseudodementia, the cognitive loss follows after the onset of MDD
(McBride & Abeles, 2000; Reynolds & Hoch, 1987; Reynolds et
al., 1988). Disorders that cause dementia such as Alzheimer’s
disease also tend to have characteristic neuropsychological profiles
that help distinguish dementia from depression (Kasahara et al.,
2006; Naugle, Cullum, & Bigler, 1998). There has been considerable debate as to whether depression serves as a prodromal stage
(Broe et al., 1990) or a risk factor for dementia (Barnes, Alexopoulos, Lopez, Williamson, & Yaffe, 2006; Devanand et al., 1996;
Geda et al., 2006). For example, in a large cohort (N ⫽ 1,070) of
community living people over the age of 65, pseudomentia showed
a 0.6% prevalence rate, and of the six persons diagnosed with
pseudodementia, only two developed dementia (Copeland et al.,
1992). However, in a separate large cohort (N ⫽ 1,070) of persons
age 60 years or older who were part of a dementia registry,
baseline depressed mood was found to increase the risk of incident
dementia (Devanand et al., 1996). Also, Saez-Fonseca, Lee, and
Walker (2007) found a relative risk of 3.929, 95% CI
[1.985, 7.775], for the development of dementia in patients with
DEPRESSION SEVERITY AND NEUROCOGNITIVE FUNCTION
depression and pseudodementia on a 5- or 7-year follow-up examination. Further, a recent study suggested that patients with
late-life depression, even after successful antidepressant treatment,
were more likely to be diagnosed with mild cognitive impairment
(nonamnestic or amnestic subtype) or dementia, relative to a
matched control group (Bhalla et al., 2009). Thus, there is a
complex association between depression and dementia (for a comprehensive review of the relationship between depression,
pseudodementia, and dementia, see Butters et al., 2008).
Neurocognitive Studies of MDD
Cognitive dysfunction related to MDD (see Table 1 for details
of the studies discussed in this section) has been reported in some,
but not all studies (Gorlyn et al., 2006; F. C. Murphy, Michael,
Robbins, & Sahakian, 2003; Shenal et al., 2003) that examined
varying degrees of depression severity (Landro, Stiles, & Sletvold,
2001). In a study comparing 22 patients with nonpsychotic MDD
to 30 healthy normal participants, Landro and colleagues (2001)
found that those with MDD performed significantly worse in the
domains of attention, working memory, verbal long-term memory,
and verbal fluency. The depressed group scored more than 1.5
standard deviations lower in attention and working memory,
1.0 standard deviation lower in verbal long-term memory, and 0.5
standard deviations lower in verbal fluency. This is consistent with
other findings indicating impairment in verbal fluency and cognitive flexibility (Beblo, Baumann, Bogerts, Wallesch, & Herrman,
1999; Leuchter et al., 2004). For example, Beblo et al. (1999)
found that 41 depressed patients, compared to a control group,
performed worse (i.e., 1 standard deviation) on verbal fluency
(Controlled Oral Word Association Test; Benton & Hamsher,
1983) and design fluency. Another study comparing patients with
bipolar disorder or MD, and controls found the MDD group scored
lower on a measure of nonverbal memory from the CANTAB
battery (i.e., Match to Sample Task) relative to the control group,
but the difference was minimal (Sweeney, Kmiec, & Kupfer,
2000).
Clinically, the relationship between MDD and global cognitive
function may be modulated by depression severity. For example,
one report noted that patients who required hospitalization for
depression were found to have greater cognitive difficulties
(Rohling, Green, Allen, & Iverson, 2002). Even during euthymic
and remission phases, the effects of depression severity may linger, influencing cognitive effectiveness. It has been postulated that
due to the negative effects of the MDE, the brain, during the
euthymic phase, is in a period of healing and may not function at
its normal level (Kessing, 1998; Paradiso, Lamberty, Garvey, &
Robinson, 1997). However, Hammar et al. (2003) found in a
cohort of 21 patients (18 hospitalized) with MDD that cognitive
functioning returned to normal during remission. Depression severity may particularly impact aspects of memory. In research
comparing 26 patients with MDD, 28 with minor depression,
and 38 healthy controls, those with MDD were significantly more
impaired on tests of verbal recall and set maintenance relative to
the other groups. Those with minor depression were found to be
mildly impaired on a measure of executive functioning (ElderkinThompson et al., 2003), relative to healthy controls. Minor depression, as defined in the DSM–IV–TR (American Psychiatric Association, 2000), is similar to MDD, except it consists of having only
27
two to five depressive symptoms (one symptom must be either sad
mood or anhedonia) for a minimum of 2 weeks. In the above study
by Elderkin-Thompson et al. (2003), working memory was assessed with the Digit Span subtest of the revised Wechsler Memory Scale (Wechsler, 1987) and executive functioning was assessed with a modified version of the Wisconsin Card Sorting Test.
We found it interesting that other research has suggested that those
with minor depression perform as well as controls on cognitive
measures (Airaksinen, Larsson, Lundberg, & Forsell, 2004).
Even though much of the above information suggests that MDD
is negatively associated with cognitive functioning, some research
has disagreed with that relationship (Austin, Mitchell, & Goodwin,
2001). Particularly in young adult patients with mild to moderate
depression, cognitive compromise seems to be rare. For example,
Wang et al. (2006) found no differences in performance on a
comprehensive battery of neuropsychological tests including the
CANTAB, Trail Making Test Parts A and B, Digit Span, Continuous Performance Test, verbal fluency, the WCST, and the Category Test between mild to moderate depressed (N ⫽ 123, based on
DSM–IV; American Psychiatric Association, 1994, criteria and the
Beck Depression Inventory [BDI]; Beck, 1978) and healthy young
adult control (N ⫽ 36) cohorts.
Gorlyn et al. (2006) examined performance on the Wechsler
Adult Intelligence Scale (3rd ed., WAIS–III; Wechsler, 1997) in
121 severely depressed patients (based on DSM–IV criteria and the
HAM–D) and 41 healthy controls. The depressed group performed
worse on the performance IQ subtests, particularly those that were
timed (e.g., Coding, Symbol Search), which also resulted in low
scores on the processing speed index. In a longitudinal study
(Cysique et al., 2007) assessing the impact of depression on
cognitive functioning in a cohort of HIV positive men (N ⫽ 227),
no relationship was found between mild trait depression and objective neuropsychological measures, although a relationship was
found between trait depression and subjective cognitive complaints. In the Cysique et al. (2007) study, neuropsychological
performance was analyzed using normative adjusted T scores from
the revised version of the Wechsler Adult Intelligence Scale
(WAIS–R; Wechsler, 1981) and the Halstead–Reitan Battery
(Heaton et al., 1991). Moreover, in a study of 30 patients with
MDD, executive function was found to improve after remission
was achieved (Biringer et al., 2005). Further research may help
elucidate the relationship between depression severity and neurocognitive functioning as well as discern if normalization of function is time dependent postremission.
Attention and Memory
Both automatic and effortful attention can be negatively affected
by MDD. In a study (Farrin, Hull, Unwin, Wykes, & David, 2003)
of 102 men with MDD compared to 59 controls, the depressed
group performed significantly worse on the Sustained Attention to
Response Task (SART; Robertson, Manly, & Andrade, 1997), a
computer-administered test of visual attention. Also, impairment
in divided attention, defined as difficulty in attending to both visual
and auditory stimuli, was found to be predictive of the outcome of
the depressive course in one study (Majer et al., 2004). In the study
by Majer et al. (2004), the analyses controlled for age, gender,
years of education, depression severity (as rated on the HAM–D),
duration of illness, duration of hospitalization, type of antidepres-
28
MCCLINTOCK, HUSAIN, GREER, AND CULLUM
sant (activating or sedating), and other psychotropic medications
(neuroleptic, mood stabilizer, tranquilizer).
Depression may also negatively impact different types of memory, including explicit, implicit, short term, long term, and working
memory (Nitschke, Heller, Etienne, & Miller, 2004; Wang et al.,
2006). Performance on verbal memory tasks may result from poor
frontal-temporal lobe functioning, preoccupation with negative
thoughts, or decreased processing speed (Nebes et al., 2000). In a
study examining the relationship of the BDI (Beck, 1978) to
different versions of the California Verbal Learning Test (CVLT;
e.g., adult, child; Delis, Kramer, Kaplan, & Ober, 1987; Delis,
Kramer, Kaplan, & Ober, 1994), once adjusted for age, gender,
and intelligence, depression accounted for only 2% of the variance
in the CVLT score (O’Jile, Schrimsher, & O’Bryant, 2005). Contrary to the above, persons with MDD have been found to score
between 0.5 and 1 standard deviation (corrected for age, education,
and gender) below the normative population on the CVLT List A
total Trials 1 to 5 (Otto et al., 1994). Behaviorally, MDD may also
decrease individuals’ abilities to carry out instrumental activities
of daily living, which may affect patients’ abilities to comply with
cognitive testing (Kiosses & Alexopoulos, 2005) Thus, there is an
indication that those with MDD may not perform as well as those
without MDD on measures of attention and/or memory.
Executive Functioning
Executive functioning (EF) has been defined as “the ability to
maintain an appropriate problem-solving set for attainment of a
future goal” (Welsch & Pennington, 1988, p. 201). Expanding this
definition, Welsch, Pennington, and Groisser (1991) added that EF
includes the abilities of planning, performing organized searches,
and controlling impulses.
EF can be negatively affected by depression as it has been shown
to decrease initiation and problem solving (Elderkin-Thompson,
Mintz, Haroon, Lavretsky, & Kumar, 2006; Harvey et al., 2004;
Kiosses, Klimstra, Murphy, & Alexopoulos, 2001), affect planning
(Rogers et al., 2004), impair verbal fluency (Henry & Crawford,
2005), and impede cognitive flexibility (Baudic, Tzortzis, Barba, &
Traykov, 2004; Butters et al., 2004). Although there is no consensus
on the mechanisms of action, it is believed that depression is associated with frontal cortical impairment, which in turn leads to executive
dysfunction because EF is mainly governed by the frontal cortices
(Alvarez & Emory, 2006; Bravers et al., 1997; Carpenter, Just, &
Reichle, 2000; Dolan et al., 1994; Kaiser et al., 2003).
Research has indicated that depression severity may play a role
in the degree of executive impairment (Taylor, Wagner, & Steffens, 2002). Although the Taylor et al. (2002) study included
patients who were diagnosed with MCI at baseline, in a small
cohort (N ⫽ 13) study, depression severity, as measured by the
HAM–D (Hamilton, 1960) was found to be an independent predictor of total errors, perseverative responses, and failure to maintain set on the WCST (Martin, Oren, & Boon, 1991). Contrary to
this finding, Harvey and colleagues (2004) found no relationship
between depression severity and the WCST in 22 depressed patients. Also, in one study, those with MDD were found to perform
similarly to those with schizophrenia on the California Card Sorting Test (Delis, Squire, Bihrle, & Massman, 1992). Both groups
were found to be impaired in generating spontaneous sorts and
they were unable to identify some of the sorting principles in the
structured sort. The variable findings between the studies suggest
that the relationship between EF and depression severity may be
moderated by the EF measure used.
Influence of Medications and Comorbid Illness on
Cognitive Function in MDD
It is important to consider not only the positive influence that
antidepressant medication may have on cognitive function in depression, but also the potential adverse effects of pharmacotherapy. Here
again, the impact of chronicity of depression is important because
there is some evidence to suggest that long term and/or repeated
exposure to some antidepressant medications may adversely affect
cognitive function. For example, tricyclic antidepressants (e.g., amitriptyline, nortriptyline) may worsen some cognitive processes such as
reaction time and information processing speed, possibly due to the
anticholinergic effects of these medications, whereas it has been noted
that Selective Serotonin Reuptake Inhibitor (SSRI) may hold some
benefit for cognitive function, particularly in older adults (Brooks &
Hoblyn, 2007). Similarly, medications for specific symptoms of depression, such as hypnotics used for insomnia, may independently
impair cognitive function.
A related concern is the impact of comorbid diseases and depression. Depression is highly comorbid with many other chronic illnesses
that can exert independent adverse effects on cognitive function.
Increased age can be a contributing concern because the likelihood of
comorbidity increases, as does the likelihood of polypharmacy, which
may introduce additional adverse pharmacological effects on cognitive function. Psychiatric comorbidities such as substance abuse and
anxiety are important to consider in depressed patients because of
their independent potential effects on cognition. For example, substance abuse has been associated with both neurophysiological
changes in frontostriatal brain regions, as well as objective cognitive
impairments (Bechara & Martin, 2004; Lamers, Bechara, Rizzo, &
Ramaekers, 2006; Robbins, Ersche, & Everitt, 2008; Salo, Ursu,
Buonocore, Leamon, & Carter, 2009). Furthermore, treatments for
substance use disorders, such as methadone and nicotine replacement
therapies have also been associated with impaired cognitive function
in some studies (Soyka et al., 2008; Spiga, Lintas, & Diana, 2008).
Similarly, anxiety, also known to be highly comorbid with depression,
can affect cognitive processing in some cases, and is often treated with
benzodiazepines, which have known negative effects on cognitive
function (Buffett-Jerrott & Stewart, 2002). In these cases, both the
disease state and its treatment may contribute to cognitive impairments.
Many other general medical chronic diseases, such as diabetes and vascular illness, are highly comorbid with depression
and can also independently impact cognitive function. Diabetes
has been associated with some cognitive impairments (Awad,
Gagnon, & Messier, 2004; Cukierman-Yaffe et al., 2009), and
these deficits may worsen with increasing age and/or the presence of vascular disease or depressive symptomatology (Awad
et al., 2004). Vascular illness is another example of a general
medical condition that is highly comorbid with depression and
associated with independent adverse effects on cognitive function (Roman et al., 2004; Sachdev et al., 2004; Waldstein et al.,
2003). The potential cumulative and additive cognitive impairments arising from comorbid psychiatric and medical condi-
DEPRESSION SEVERITY AND NEUROCOGNITIVE FUNCTION
tions, as well as their treatments, must be considered when
evaluating cognitive function in depression.
Summary of Findings
Depression is a significant clinical disease with varying levels of
severity, each associated with degrees of impairment in the areas
of social, functional, and interpersonal abilities. However, depression has been inconsistently associated with neurocognitive functioning (Gualtieri et al., 2006) and there is limited understanding
regarding the relationship between depression severity and neurocognitive sequelae. Although research has shown detrimental effects in the domains of attention, learning and memory, and EF
related to depression, there is disagreement as to the mediators of
neurocognitive impairment, and for that matter, the mechanisms
underlying the neurocognitive impairment. Several aspects of depression severity have been associated with more pronounced
cognitive impairment, such as increased symptom severity at the
time of neuropsychological testing. The presence of depression
with psychosis may negatively impact neuropsychological domains such as EF, verbal and visual memory, and psychomotor
skills to a greater extent relative to depression without psychotic
features (Reichenberg et al., 2008). In addition, recurrent depression has been associated with worse cognitive performance compared to single-episode depression (Kessing, 1998), and longer
depressive episodes have been associated with greater impairments
on some aspects of executive function compared to shorter episodes (Grant et al., 2001). Age of onset of depression (Driscoll et
al., 2005) is a more complicated factor, with some evidence
suggesting that an early onset depression (i.e., onset before age 55)
is associated with poorer cognitive function (Majer et al., 2004),
although other evidence suggests that late-onset depression (i.e.,
onset at age ⱖ 55) is associated with poorer cognitive function
(Elderkin-Thompson et al., 2006; Rapp et al., 2005). However,
many studies have found no relationship between course of illness
factors and cognitive performance in depression (Biringer et al.,
2005; Naismith et al., 2003; Porter et al., 2003), and still more have
not included assessments of such a relationship. It is clear that
there is much heterogeneity on severity-related factors (i.e., level
of symptom severity, course of illness characteristics) within samples assessing cognitive function in MDD, as well as substantial
variability in the consideration of severity among studies, resulting
in the need to further explore this important issue.
Future Directions
Individual studies examining cognitive deficits associated with
MDD tend to not provide consistent information regarding depression severity (Zakzanis et al., 1999), which has limited the understanding of the relationship between depression and neurocognitive function (Naismith et al., 2003). This may be attributed to
many factors such as limitations in quantifying the level of depression severity and deciding how to measure depressive symptoms (Gullion & Rush, 1998). Although there is limited information regarding the cognitive effects associated with depression
severity, this paucity in research demonstrates the importance of
conducting further research in the relationship between cognitive
functioning and intradomain specific depressive factors (Ebmeier,
Donaghey, & Steele, 2006).
29
Although depression can negatively impact cognitive functioning in some cases (Shenal et al., 2003), it is important to understand what specifically about MDD is affecting cognitive abilities.
Furthermore, the factors associated with cognitive dysfunction in
depression are not well understood. There is considerable variability and not all persons with MDD show reduced cognitive performance, although estimates of dysfunction have been found to
range from mild to severe in the depressive population (Elliott,
1998; Veiel, 1997). For example, is the variability in cognitive
performance related to the number of depressive episodes, the
severity of the major depressive episode, or the MDD subtype (i.e.,
melancholic, atypical)? Also, factors such as length of the depressive episode, onset of the depressive episode, and individual factors such as age, education, cognitive reserve, or genetic predisposition to depression, could play a role in the development of
cognitive impairment secondary to depression.
Prior research has helped increase the understanding of the complex relationship between cognitive function and MDD; however, this
understanding has been limited by small sample sizes, limited sociodemographic information (e.g., socioeconomic status, parental education), limited neurocognitive evaluations, and the use of either selfreport or clinician-rated depressive instruments as opposed to both. To
Table 2
Recommendations for Future Study Directions
1. Comprehensively characterize the sociodemographics of the study
sample
(a) Provide demographic adjusted neurocognitive scores
(b) Allows for study of sociodemographic moderating factors
2. Include a comprehensive neuropsychological assessment that includes
measures of
(a) Learning and memory (both verbal and visual)
(b) Visuospatial abilities
(c) Working memory (both verbal and visual)
(d) Attention/concentration
(e) Psychomotor speed
(f) Executive functioning
(g) Language functions
(h) Intelligence or estimate of intellectual functioning
(i) Social cognition
(j) Subjective cognitive complaints
3. Base psychiatric diagnoses of depression on standardized, research
diagnostic criteria
(a) Allows for establishing universally accepted diagnosis
(b) Establishes homogenous groups
(c) Collects comorbid psychiatric illnesses
(d) Provides general assessment of global functioning
4. Utilize both clinician-rated and self-rated depression severity
instruments that are identical in content
(a) Provides a mechanism to assess the relationship between objective
and subjective clinical ratings with neurocognitive functioning
(b) Identical clinician-rated and self-rated measures increases
confidence of the ratings by reducing confounding and unidentical items
5. Comprehensively characterize the depressive illness
(a) Specify the depressive episode subtype (i.e., melancholic, atypical)
(b) Specify the number of depressive episodes
(c) Specify the duration of the current depressive episode
(d) Specify age of onset of depressive episode
6. If diurnal variation is present, then provide assessment at opposite
time (i.e., if mood worse in the morning, then test later in the day)
7. Include neurobiological methods such as neuroimaging (i.e., fMRI) or
neurochemical (i.e., cortisol) measures
Note.
fMRI ⫽ functional MRI.
30
MCCLINTOCK, HUSAIN, GREER, AND CULLUM
address these limitations, future investigations (see Table 2)
may benefit from better characterizing the sociodemographic
and clinical characteristics of the sample to account for potential moderating factors (De Santi et al., 2008; Manly, 2008;
Manly & Echemendia, 2007; Marcopulos & McLain, 2003;
Salthouse, 2007). Regarding depression severity, this could be
enhanced by utilizing both self-report and clinician-rated depressive symptom severity instruments to help clarify the relationship between objective and subjective ratings on cognitive
abilities. Also, the use of a standard neuropsychological battery
that measures multiple-cognitive functions and includes demographic adjusted data would help to minimize age and education
confounds. Given the limitations in prior studies and newer
available methods, further research is needed to help clarify the
relationship between major depressive disorder and cognitive
functioning.
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Received October 30, 2008
Revision received June 1, 2009
Accepted August 4, 2009 䡲