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Longitudinal assessment of

neuropsychological function in major


depression
Katie M. Douglas, Richard J. Porter

Neuropsychological impairment is a core component of major depression, yet its relationship


to clinical state is unclear. The aims of the present review were to determine which
neuropsychological domains and tasks were most sensitive to improvement in clinical state
in major depression and to highlight the methodological issues in such research. Studies
that included a baseline and at least one follow-up neuropsychological testing session in
adults with major depression were identified using MEDLINE, Web of Science and
ScienceDirect databases. Thirty studies were included in the review. Findings in younger
adult populations suggested that improvement in mood was most strongly related to
improved verbal memory and verbal fluency, while measures of executive functioning
and attention tended to remain impaired across treatment. In late-life major depression,
improved psychomotor speed was most closely related to treatment response, but there
was much inconsistency between study findings, which may be due to methodological
issues. In major depression, particular neuropsychological domains are more strongly
related to clinical state than others. The findings from the present review suggest that the
domains most sensitive to clinical state are verbal learning and memory, verbal fluency
and psychomotor speed. In contrast, measures of attention and executive functioning
perhaps represent more trait-like markers of major depression. With further methodologically
sound research, the changes in neuropsychological function associated with treatment
response may provide a means of evaluating different treatment strategies in major
depression.
Key words: executive function, major depressive disorder, memory, neuropsychological
function, remission.
Australian and New Zealand Journal of Psychiatry 2009; 43:11051117

Among the many disabling features of major depressive


disorder (MDD) is neuropsychological dysfunction,
which is increasingly becoming recognized as a core
component of the disorder [1]. A fundamental question
regarding this neuropsychological dysfunction is whether

Richard J. Porter, Professor (Correspondence); Katie M. Douglas, PhD


Candidate
Department of Psychological Medicine, University of Otago,
Christchurch, PO Box 4345, Christchurch, New Zealand. Email:
richard.porter@otago.ac.nz
Received 14 June 2009; accepted 13 August 2009.

2009 The Royal Australian and New Zealand College of Psychiatrists

it is part of the underlying and stable neurobiological


vulnerability to MDD (i.e. a trait) or whether it occurs
only during episodes of depressed mood (i.e. state).
Alternatively, it is possible that functions subserved by
certain areas of the brain may be more sensitive to clinical state, while other functions are less changeable but
more clearly trait-related.
Longitudinal description of the pattern of neuropsychological impairment in MDD during episodes, and
during and following treatment may help to answer these
fundamental questions. In addition, longitudinal assessment would be useful for the following reasons. First, it

1106

K.M. DOUGLAS, R.J. PORTER

may further elucidate changes in brain function in MDD


both during episodes and following recovery. Second,
measuring changes in neuropsychological function may
be helpful in assessing the effects of various treatments
including both pharmacological and psychological.
Measuring neuropsychological changes could provide a
more objective marker of treatment response and may
show change or differentiation between treatments at an
earlier time point than traditional depression rating
scales. The ability to measure response or non-response
to treatment at an early stage could potentially also
enable clinicians to either increase dosing or alter treatment in order to determine the best treatment for the
patient as quickly as possible.
The aims of the present review were therefore as follows: (i) to examine change in neuropsychological function in MDD and its relationship to symptomatology and
to further examine which domains of function appear to
be sensitive to improvement in clinical state; (ii) to examine which neuropsychological domains or tests would be
most likely to be useful in determining treatment response
in MDD; and (iii) to examine methodological issues in
studies examining change in neuropsychological function over time in MDD.
We reviewed all available literature in which neuropsychological testing and clinical measures of severity of
MDD at baseline and after a specied amount of time
after treatment, were conducted.

Methods
Search strategy
Up to 1 May 2009, electronic database searches were carried out
for relevant papers, utilizing MEDLINE and Web of Science. In the
initial search, the terms: major depressive disorder or major
depression or depression and neuropsychological impairment or
neuropsychological function or cognitive impairment or cognitive function were used. To enable the inclusion of more recent
articles, ScienceDirect was also searched using the aforementioned
keywords in the abstract, title, keywords eld. We also checked the
reference lists of all the relevant papers and the Web of Science was
used to review the articles that had cited the relevant articles found
using these search strategies.

Inclusion criteria
We selected only those articles involving assessment of neuropsychological function and depression severity at least twice during treatment of a major depressive episode (unipolar or bipolar) in younger
adult or late-life samples.

Exclusion criteria
Reasons for exclusion were: (i) use of a depressed sample with
comorbid major medical, neurological, or endocrinological conditions
(the number of studies in this criterion is unknown because many studies of disorders such as dementia or Parkinsons disease involve comorbid depression); (ii) inclusion of patients who were being treated with
electroconvulsive therapy (ECT; a review of all papers conducting
follow-up neuropsychological testing in ECT patients has previously
been published [2]); (iii) lack of comparison of change in neuropsychological function between test occasions (n = 3); or (iv) lack of presentation of results for described neuropsychological testing procedures
(n = 2). For the latter exclusion condition, the authors were contacted
via email and asked to send their neuropsychological data, but no
replies were received. All studies were limited to English-language
publications.

Results
Study characteristics
Thirty studies met the inclusion criteria (Table 1). Of these studies, 18
included healthy controls but two of these studies only tested the controls at baseline [3,4]. The analyses conducted in these studies were
able to be categorized under ve main headings (some studies included
more than one type of analysis), as follows.
(1) Those that measured overall change in mood rating scales and
overall change in neuropsychological function, but did not report the
direct relationship between these two measures [59]. In the Majer
et al. and Reppermund et al. studies, patients had been classed as
remitters versus non-remitters (and responders vs non-responders), but
this information was used only for baseline neuropsychological comparisons and predictions [6,7].
(2) Those in which all or nearly all patients were deemed to be remitters (or responders) at follow up. For these studies, the change in neuropsychological function over time was presented and, in some cases,
compared with healthy controls [1016].
(3) Those in which only the neuropsychological performance of the
remitters (or responders) was presented and, in some cases, compared
with healthy controls and/or the depressed group as a whole [3,1721].
(4) Those that categorized patients into remitters (or responders) and
non-remitters (or non-responders) and compared the change in neuropsychological function between the two groups over time [3,4,2128].
(5) Those that correlated change in mood rating scales with change
in neuropsychological performance over time [3,18,21,2932].
The latter two types of studies are more informative than the others
when examining the association between treatment response and
changes in neuropsychological function. Thus, more of an emphasis
will be placed on these studies in the review. The results from the review
(Table 1) will be discussed in detail in the subsequent sections, followed
by a discussion of the methodological inconsistencies between these
studies.

P = 41
C = 20

P = 30
C = 50

P = 20
C = 26

P = 25
C = 13

P = 20

P = 48

Beblo et al.
(1999) [22]

Biringer et al.
(2005,2007)
[21,3]

Constant et al.
(2005) [29]

Gallagher
et al. (2007)
[23]

HerreraGuzman et al.
(2008) [28]

Jaeger et al.
(2006) [5]

Depressed adult studies

Study

MDD
Incl. psychotic
Inpatient

UNI MDD
Non-psychotic
Outpatient

UNI MDD
Non-psychotic
Outpatient

UNI MDD
Non-psychotic
Outpatient

UNI MDD
Inpatient/
outpatient

MDD
Inpatient

Type of MDD

HDRS-17 = 16

HDRS-17 = 25

BDI = 29.3
HDRS-17 = 21
MADRS = 29

BDI = 26

HDRS-17 = 22

BDI = 25
CDS = 14
MADRS = 16

Baseline
mood
rating

P = 40

P = 24

P = 33
C = 31

P = 48
C = 49

P = 35
C = 35

P = 56
C = 56

Age
(years)

Table 1.

6 months

8 weeks

26 months

3 weeks
7 weeks

2 years

13 months

Follow up

Reviewed studies

Group improvement
on HDRS score at
FU.

Response (n = 12)
>50% reduction on
HDRS at FU

Remission (n = 11)
<8 on HDRS at FU.

Correlation
between BDI and
neuropsyc.
Comparison of
more depressed
vs less depressed
at FU.

Correlation
between HDRS +
neuropsyc.
Recovery (n = 17)
7 on HDRS at FU.

Response (n = 12)
<17 on BDI and
50% reduction on
BDI at FU.

Treatment
outcome
measures

(Continued)

Improvement at FU in domains of attention,


working memory, and word fluency. No
analysis of correlation between these
improvements and HDRS score done.

Response: significant greater improvement in


visual memory than non-responders
(responders were worse to begin with).

Remission: greater improvement in verbal


declarative memory compared to those who
remained depressed at FU.

Significant correlation between BDI score


and psychomotor speed on Stroop task
between baseline and 3 weeks in depressed
group. No further at 7 weeks.
More interference for words with negative
valence in more depressed group vs less
depressed group.

2005 analysis: significant correlation between


HDRS and composite score on executive
functioning.
Recovery: executive functioning improved to
level of controls except Stroop task and
semantic fluency.
2007 re-analysis: significant correlation
between HDRS and verbal memory but
not attention (executive function), visual
memory or psychomotor speed.
Recovery: improvement in verbal memory to
control level at FU and performed better than
in their depressed state in attention, visual
memory and psychomotor speed.

Response: significant improvement in design,


phonological and verbal fluency compared to
non-responders.

Summary of main ndings

NEUROPSYCHOLOGICAL CHANGE IN MDD

1107

UNI MDD
Outpatient

P = 75

P = 53
C = 13

P = 23
C = 15

P = 22
C = 33

P = 17

Reppermund
et al. (2007)
[24]

Reppermund
et al. (2009)
[7]

Trichard et al.
(1995) [31]

Vythilingam
et al. (2004)
[10]

Wroolie et al.
(2006) [11]

HDRS-21 = 25

HDRS-21 = 25

BRMS:
UNI = 20,
BP = 17,
DYS = 17,
schiz.AD = 19

UNI MDD
Non-psychotic
Outpatient
Females only

HDRS-21 = 21

YDI = 34

UNI or BD MDD MADRS = 39


Inpatient

UNI MDD
Inpatient

MDD
Inpatient

MDD incl. UNI,


BD, DYS and
schiz.AD
Inpatient

P = 80
C = 62

Neu et al.
(2001) [30]

UNI or BD MDD HDRS-21 = 29


Incl. psychotic
MADRS = 34
Inpatient
BDI = 26

Type of MDD

P = 73

Majer et al.
(2004) [6]

Study

Baseline
mood
rating

P = 56

P = 41
C = 34

P = 47
C = 41

P = 44
C = 46

P = 45

P = 47
C = 52

P = 46

Age
(years)

Table 1.

3 months

7 months

4 weeks

Approx. 9 weeks
6 months

13 months

Approx.
3 months

Approx. 4 weeks
6 months

Follow up

(Continued)

Remission (n = 15)
7 on HDRS at FU.

Response (all) =
in YDI score.

Correlation
between MADRS
and neuropsyc
(all euthymic at
FU).

Remission (n = 43)
9 on HDRS at FU.

Remission (n = 51)
9 on HDRS at FU.

Correlation
between BRMS
and neuropsyc.

Response
(n = 35) = 50%
reduction on HDRS
at FU. Remission
(n = 39) <10 on
HDRS at FU.

Treatment
outcome
measures

Significant improvement at FU testing found


in immediate verbal and visual memory (both
using the WMS-III) and executive functioning
(TMT-B). No separation between remission
and non-remission.

Response: significant improvement in verbal


memory.

Significant correlation: MADRS + verbal


fluency. Depressed groups performance on
verbal fluency reached that of controls after
successful treatment. Performance on Stroop
task remained significantly worse than
controls.

After correcting for practice effects, was


significant improvement in some executive
functioning tests (verbal and semantic
fluency, working memory). Classification of
remission used to compare baseline
neuropsyc only.

Remission: significant improvement in


psychomotor speed compared to nonremission group.

No correlation: BRMS + any cognitive


domains (verbal and visual learning and
memory, verbal fluency, psychomotor speed).

As a group, depressive ratings were


significantly reduced at FU, yet no change in
neuropsyc with exception of improved
performance on the letter cancellation task.
Classification of response/remission used to
compare baseline neuropsyc only.

Summary of main ndings

1108
K.M. DOUGLAS, R.J. PORTER

P = 64

Zobel et al.
(2004) [25]

P = 20
C = 20

P = 19
C = 15

P = 56
C = 40

Abas et al.
(1990) [12]

Beats et al.
(1996) [13]

Bhalla et al.
(2006) [14]

Depressed late-life studies

P = 19

Young et al.
(2004) [8]

Study

UNI MDD
Non-psychotic
Inpatient/
outpatient
Sample
>60 years

MDD
Inpatient/
outpatient
Sample
>60 years
7 had onset
<60 years

Endogenous
MDD/BD
Inpatient/
outpatient
Sample
>60 years
10 had onset
<50 years

UNI MDD
Non-psychotic
Inpatient

BD with
residual MDD
symptoms (17
with current
MDD)
Outpatient

Type of MDD

HDRS-17 = 20

MADRS = 40
HDRS-17 = 30

MADRS = 31

HDRS-17 = 25

HDRS-17 = 18
MADRS = 23

Baseline
mood
rating

P = 72
C = 70

P = 72
C = 69

P = 70
C = 68

P = 47

P = 49

Age
(years)

Table 1.

1 year

Recovery

Recovery

4 weeks

3 weeks
6 weeks

Follow up

(continued)

Remission (all) 10
on HDRS.

Recovery (all) <10


on MADRS.

Recovery (all), as
deemed by
psychiatrist and
relatives.

Correlation
between HDRS
and neuropsyc.

HDRS and
MADRS scores
from baseline.

Treatment
outcome
measures

(Continued)

Patients improved to the same extent as


controls in all five neuropsyc domains, still
remaining below controls at FU.
Remission: 45% of patients cognitively
impaired at 1 year compared with 30% at
baseline. Impairment greatest in visuospatial
ability, information-processing speed and
delayed memory.

Recovery: improvement across all tasks


(attention, executive functioning, processing
speed, visuospatial learning and memory) to
level of controls except for some latency/
reaction time measures.

Recovery: significant improvement on pattern


recognition and Kendrick Object Learning
Task accuracy to level of controls.

No correlation: HDRS + any cognitive


domains (verbal learning and memory and
attention).

Symptoms of MDD and performance on


tasks of spatial working and recognition
memory and verbal fluency improved
compared to placebo. No analysis of
correlation between HDRS or MADRS
and neuropsyc done.

Summary of main ndings

NEUROPSYCHOLOGICAL CHANGE IN MDD

1109

P = 45
C = 20

P = 53

P = 26

P = 444

P = 42
C = 15

P = 67

P = 39
C = 19

Butters et al.
(2004): Study
I [26]

Devanand
et al. (2003)
[27]

Doraiswamy
et al. (2003)
[32]

Gallassi et al.
(2006) [17]

Lee et al.
(2007) [16]

Nebes et al.
(2000) [18]

Butters et al.
(2000) [15]

Study

UNI MDD
Non-psychotic
Outpatient
Sample
>60 years

UNI MDD
Non psychotic
Inpatient/
outpatient

UNI MDD
Outpatient
Sample
>60 years

MDD
Outpatient
Sample
>50 years
All late-onset

UNI MDD
Outpatient
Sample
>50 years

MDD
Inpatient/
outpatient
Sample
>65 years

MDD
Inpatient/
outpatient
Late-life
patients

Type of MDD

HDRS-17 = 23

MADRS = 21

HDRS = 26
GDS = 25

HDRS-24 = 25

HDRS-17 = 15
CGI = 3.4

HDRS-17 = 22

HDRS-17 = 22

Baseline
mood
rating

P = 71
C = 70

P = 68

P = 68
C = 69

P = 68

P = 72

P = 72

P = 73
C = 70

Age
(years)

Table 1.

12 weeks

1 year

6 months

12 weeks

12 weeks

1214 weeks

12 weeks

Follow up

(Continued)

Remission (n = 20)
10 on HDRS for 3
consecutive weeks.
Correlation between
HDRS and
neuropsyc.

Remission (all) <9


on MADRS at FU.

Remission (n = 33)
11 on HDRS for
those over 65 years
and 7 for those
under 65 at FU.

Correlation
between HDRS
and neuropsyc.

Response (n = 17)
50% decline on
HDRS and CGI = 1
or 2.

Recurrence (n = 8)
DSM-IV MDD and
15 HDRS for
3 weeks.

Remission (all) 10
on HDRS for
3 weeks.

Treatment
outcome
measures

Remission: improvement on tasks of working


memory and processing speed. But amount
of improvement was no greater than that
seen in controls with repeat testing. Nonremitters were not retested on neuropsyc
tasks. No correlation: HDRS and working
memory or processing speed in remitters.

Remission: 55% of patients had MCI at


baseline and 45% of patients still had MCI at
FU.

Remission: improvement on MMSE and verbal


and visual memory at FU but still differed from
controls in a few tasks requiring more cognitive
effort (logical memory and associated verbal
learning). Remitters not compared to nonremitters on neuropsyc functions.

Significant correlation: HDRS and DSST


and SLT for patients treated with sertraline
and nortriptyline, but not for patients treated
with fluoxetine. Correlation was strongest for
sertraline.

Response: improvement on DSST with


sertraline but decline in non-responders.
Difference between groups significant

Recurrence:- did not differ on total DRS at


baseline or after treatment response, or on
any subscales compared with nonrecurrence.

Remission: small improvement in DRS over


treatment due to small changes across
subscales, not significant improvement on 1
domain. On remission, performance still
below controls.

Summary of main ndings

1110
K.M. DOUGLAS, R.J. PORTER

P = 61
C = 40

P = 30
C = 15

P = 18
C = 22

OBrien et al.
(2004) [20]

Portella et al.
(2003) [4]

Savaskan
et al. (2008)
[9]

MDD first
episode
Inpatient
Sample
>65 years

UNI MDD
Inpatient/
outpatient
Sample
>60 years

MDD and BD
Incl. psychotic
Inpatient/
outpatient
Sample
>60 years

UNI MDD
Non-psychotic
Inpatient/
outpatient
41 late-onset
MDD

Type of MDD

GDS = 9

HDRS-17 = 30

MADRS = 31

HDRS-17 = 23

P = 76
C = 77

P = 72
C = 60

P = 74
C = 73

P = 70
C = 71

Age
(years)

4 weeks

1 year

6 months

1,4 ,6,12 weeks

Follow up

(Continued)

Group improvement
in GDS at FU.

Remission (n = 21)
<8 on HDRS at FU.

Remission (n = 26)
<8 on MADRS and
not DSM-IV MDD.

Response (n = 32)
10 on HDRS at
FU.

Treatment
outcome
measures

Neuropsyc function (MMSE) significantly


improved over treatment, but no correlation
done to relate MMSE to GDS. Controls
only did baseline MMSE.

Remission: no neuropsyc function over


12 months and no differences between
remitted and non-remitted patients.

Remission: deficits in attention, working


memory, visual and verbal learning and
memory, and executive functioning persisted
at 6 months. This was the same trend as the
whole depressed group at 6 months
(remitters and non-remitters) compared to
controls. No comparison between remitters
and non-remitters was conducted.

Response no improvement in cognitive


performance after response to antidepressant
therapy. Responders not directly compared to
non-responders.

Summary of main ndings

BD, bipolar depression; BDI, Beck Depression Inventory; BRMS, BechRafaelsen Melancholia Scale; C, control; CDS, Cornell Depression Scale; CGI, Clinical Global
Impression; DRS, Dementia Rating Scale; DSST, Digit Symbol Substitution Task; DYS, dysthymia; FU, follow up; GDS, Geriatric Depression Scale; HDRS-17, 17-item Hamilton
Depression Rating Scale; HDRS-21, 21-item Hamilton Depression Rating Scale; HDRS-24, 24-item Hamilton Depression Rating Scale; MADRS, MontgomeryAsberg
Depression Rating Scale; MCI, mild cognitive impairment; MDD, major depressive disorder; MMSE, Mini Mental State Examination; P, patient; schiz.AD, schizoaffective
disorder; SLT, Shopping List Task; TMT-B, Trail-Making TestPart B; UNI, unipolar depression; WMS-III, Wechsler Memory Scale3rd edn; YDI, Yale Depression Inventory.

P = 73
C = 21

Nebes et al.
(2003) [19]

Study

Baseline
mood
rating

Table 1.

NEUROPSYCHOLOGICAL CHANGE IN MDD

1111

1112

K.M. DOUGLAS, R.J. PORTER

Neuropsychological changes during treatment of


MDD
To make the results clearer, we have separated the study ndings into
four main neuropsychological domains: executive functioning/attention, verbal memory, non-verbal memory, and psychomotor speed.

Sustained attention and executive functioning


There are inconsistencies in the literature concerning the categorization of attention and executive functioning. Furthermore, the tasks
used to measure these functions have considerable overlap [33]. We
have, therefore, combined ndings from both of these neuropsychological domains. It should also be noted that although working memory is sometimes classed under the umbrella of memory functions,
we have included it in this section too.
Short-term studies suggest that various measures of attention and
executive functioning remain impaired during treatment of and recovery from MDD. In a short-term study in a severely depressed sample,
Trichard et al. found no correlation between improvement in MDD and
performance on the Stroop task at 4 weeks [31]. After 26 months in
a moderately depressed sample, Gallagher et al. found no differences
in executive functioning/attention changes between responders and
non-responders (using spatial working memory and the Tower of London tasks) [23]. Jaeger et al., in a sample including patients with psychotic depression, found improvement in composite executive function
and composite attention scores at 6 months, but did not separate
responders and non-responders in their analysis [5]. A very much
longer-term follow-up study found a signicant correlation between
improvement in MDD and change in a composite score of executive
functioning at 2 years [21]. When re-analysing the results from that
study with a thorough operationalization procedure, however, the correlation between improvement in composite executive functioning/
attention and mood did not remain. The recovered depressed patients
performed better in attention than in their depressed states, but still not
to the level of healthy controls [3].
Overall, the studies that found relatively stable impairment in executive functioning/attention tasks conducted the follow-up neuropsychological batteries at 6 months. The second study by Biringer et al. [3]
involved follow up at 2 years and found that although tasks of attention

Two measures within the domain of executive functioning for which


there is evidence of an association with changes in depressive symptoms
are verbal and design uency. That is, the ease with which a person can
produce words or drawings given a certain set of rules. Verbal uency
tasks require patients to produce as many words as possible starting with
a certain letter (phonological) or belonging to a particular category
(semantic) in either 60 or 90 s. Design uency, in contrast, involves
producing as many different drawings or symbols within the same
amount of time. Mildly and severely depressed patients have shown
similar trends across treatment in verbal uency tasks, with performance
normalizing with successful treatment of MDD [7,8,22,31]. Two particularly strong studies directly related clinical state to change in verbal
uency. Among a battery of many neuropsychological measures, Beblo
et al. found that improvement in both verbal and design uency was the
only neuropsychological measure that was signicantly different
between responders and non-responders [22]. Furthermore, in their
severely depressed inpatient sample, Trichard et al. demonstrated a signicant correlation between improvement in mood and improvement in
verbal uency, while the Stroop task remained impaired, as already
described [31].
In summary, except for tests of uency, executive functioning/
attention has generally been shown to remain impaired during and
following treatment compared with healthy controls but shows slight
improvement if given enough time. The diverse nature of executive
functioning tasks, however, highlights the need to classify executive
functioning measures into subcategories in order to understand the precise brain mechanisms controlling each task.
Evidence of executive functioning/attention improvement in late-life
MDD is sparse. Many studies have been unsuccessful in nding a relationship between changes in executive functioning/attention and MDD
recovery. This includes a robust study by Butters et al. in which patients
whose MDD had not recurred at 1214 weeks showed no improvement
in executive functioning [26]. It appears that most studies nd executive functioning/attention throughout late-life MDD episodes to be
relatively insensitive to response to various pharmacological treatments
over 3 months [15,27], 6 months [20] and 12 months [14]. In fact, to
our knowledge, the only study that has found signicant improvement
in executive functioning/attention following recovery from depression,
among improvement across a broad range of neuropsychological tasks,
was that by Beats et al. [13].

signicantly improved with recovery from MDD, performance never


completely returned to normal. This conclusion is supported by studies

Verbal learning and memory

examining fully recovered or euthymic patients previously diagnosed


with MDD who show persistent impairment on tasks of executive functioning/attention [34], even when performance on other neuropsychological tasks is comparable to healthy controls [35,36].
Twin studies offer the ability to determine whether genetic liability
to MDD is associated with neuropsychological impairment. Christensen et al. found that broad executive functioning impairment was
present before the onset of MDD in healthy twins discordant for unipolar MDD [37], suggesting that those at high risk of MDD have
reduced executive ability; the extent of this impairment may of course
increase during episodes of MDD.

Despite a relatively small number of studies, a relationship between


improvement in verbal learning and memory (VLM) and improvement
in depressive symptoms is a fairly consistent nding. In the Biringer
et al. 2 year follow-up study, improvement in VLM was found to be
signicantly correlated with improvement in depressive symptoms [3].
Several studies with follow-up testing between 2 months and 2 years
after baseline have also shown VLM to improve signicantly more in
those who achieve remission or response to treatment compared with
those who do not [3,10,23]. These changes occurred within the context
of a comprehensive neuropsychological battery in which all other tests,

NEUROPSYCHOLOGICAL CHANGE IN MDD

including measures of executive functioning/attention and psychomotor


speed, were unrelated to clinical response. The studies had diverse samples of patients that differed in terms of hospitalization, severity, MDD
type, and number of episodes of MDD. All patients, however, were diagnosed with unipolar MDD. Measures of non-VLM (NVLM) in two of
these studies also failed to relate to clinical state [3,23]. Consistent with
these ndings, cross-sectional studies in patients who have fully recovered from MDD, or are in their euthymic phase, have found that VLM
is unimpaired compared with healthy controls [35,36].
The Beblo et al. study stands out among the others because no association between VLM and MDD recovery was shown [22]. Performance
on VLM tasks remained impaired at the follow up, which varied from
1 to 3 months after baseline. A major difference between the Beblo et al.
study and those already described above involved the mean age of the
depressed samples: being 33 years [23], 36 years [3], 41 years [10], and
56 years [22].
Two studies in late-life MDD also suggest that VLM performance is
sensitive to clinical state. In a large study Doraiswamy et al. demonstrated a signicant correlation between improvement in clinical state
and improvement on the Shopping List Task (also known as the
Buschke-Fuld Selective Reminding Test) after 12 weeks of treatment
[32]. Gallassi et al. showed improvement in VLM in remitters, but in
VLM tasks that required more cognitive effort (logical memory and
associated verbal learning) these patients still differed from controls
[17]. In addition, remitters were not directly compared to non-remitters
in that study.
A number of studies have shown persistence of VLM impairment in
late-life MDD populations [4,15,19,20,27], possibly relating to prolonged treatment responses in older populations [38]. VLM also appears
to be more severely impaired in late-life MDD patients than younger
patients [39]. OBrien et al. found an association between impaired
memory (a composite of verbal and visual memory) and hippocampal
volume at 6 months, suggesting that in late-life MDD structural changes
may be related to persisting neuropsychological impairment [20]. A
very large follow-up study in MDD that did not compare neuropsychological function between tests, however, examined predictors of neuropsychological dysfunction at baseline and at a follow-up session
several weeks later following clinical response. At follow up, length of
previous depressive history was a signicant predictor of memory function (paragraph learning) [40]. This may be related to structural changes,
such as reduced hippocampal volume, in MDD [41].

Non-verbal learning and memory


Of the studies investigating NVLM throughout an MDD episode,
four studies found differences in performance with changes in MDD
severity. In a study of patients with bipolar disorder and depressive
symptoms (some were subsyndromal for MDD), spatial recognition
memory showed signicant improvement after treatment with mifepristone [8]. Wroolie et al., in a sample of depressed female subjects, also
found an improvement in immediate visual memory after treatment
with escitalopram [11]. These two studies, however, only showed group
improvements in depressive symptoms and group improvements in

1113

NVLM, the relationship between the two was not examined. Vythilingam
et al. found that performance on the visual selective reminding test
improved in treatment responders (all patients were classied as treatment responders) even though, compared with control participants, the
depressed outpatients were not impaired on this task to begin with [10].
In a study of treatment with bupropion, Herrera-Guzman et al. found
that responders improved to a greater extent that non-responders in
NVLM after 8 weeks [28], but this was the smallest sample in the
review (responders = 12, non-responders = 8), making the ndings
somewhat preliminary. Larger neuropsychological studies that have
directly related change in NVLM to change in depressive symptomatology have not produced any signicant ndings [3,22,23].
In two late-life MDD studies that tested specically for NVLM
changes as opposed to VLM, performance on some but not all visuospatial memory tasks normalized to the level of controls on recovery
from MDD [12,13]. As well as the improvements in VLM discussed in
the previous section, Gallassi et al. found similar improvements in
visual memory in remitters yet, as stated earlier, remitters were not
compared with non-remitters [17].

Psychomotor speed
Studies generally suggest that psychomotor speed is unrelated to
MDD severity or clinical state in younger adult populations. Several
different measures of psychomotor speed have failed to show sensitivity to change in clinical state including the Stroop task reaction time
[31], the Phasic Alertness Task reaction time [22], the Digit Symbol
Substitution Task (DSST) [23], Trail-Making A [10], and the California
Computerized Assessment Package, which was developed as a specialized package to measure psychomotor speed [3]. Constant et al.,
however, found a signicant correlation between improvement in psychomotor speed after 3 weeks of sertraline treatment and MDD severity [29] but at 7 weeks, after further improvement in mood, there was
still signicant psychomotor slowing compared with controls and no
correlation with clinical improvement. Another study showing sensitivity of psychomotor speed to treatment response, among various other
neuropsychological tasks, was conducted by Reppermund et al. [24]
using the ZahlenVerbindungs-Test in inpatients. In that study remitters
showed signicant improvement in reaction time compared with nonremitters.
Overall there are some data suggesting that psychomotor speed is
sensitive to clinical state in the younger depressed population. Clinically marked psychomotor retardation is observed in adult depressed
patients and improves with successful treatment. It may be that ndings
from patients with clear psychomotor retardation are washed out when
means are analysed in groups of relatively less severely depressed
patients.
In late-life depressed samples it is more likely that baseline impairment in psychomotor speed will be observed [42,43]. Although Beats
et al. found a broad range of improvement in many neuropsychological
domains on recovery from various pharmacological treatments, measures of reaction times were the exception and remained impaired [13].
Conversely, in their sample of late-life depressed patients, Devanand

1114

K.M. DOUGLAS, R.J. PORTER

et al. found a specic improvement in psychomotor speed in responders compared with non-responders using the DSST [27]. Interestingly,
non-responders to sertraline actually worsened from baseline to follow
up. Doraiswamy et al. also found evidence of psychomotor sensitivity
to sertraline treatment response [32]. In their more severely depressed
sample, improvement on the DSST signicantly correlated with
improvement of mood. Overall, the data are more consistent in suggesting a relationship between clinical response and improved psychomotor
function in late-life MDD, as might be expected from the greater incidence of psychomotor retardation in this age-group.

Methodological issues of reviewed studies


Matched controls
A major problem with several studies was the lack of a matched
healthy control group. A control group is necessary when there are
repeated neuropsychological testing sessions to examine the extent to
which improvements in performance are related to symptom change,
as opposed to practice effects from repeated administration. Even if
parallel forms are used, improvement can still occur due to enhanced
learning strategies. This issue can be controlled for only if controls
perform equivalent testing sessions to the patient group.
The control group should also be appropriately matched to the
patients, bearing in mind that many demographic factors may affect
neuropsychological function. These factors include gender [44], age and
education [45], and phase of menstrual cycle [46,47]. In addition, nonpsychiatric related exclusion criteria (such as pregnancy, previous head
injury, or serious medical conditions) should be the same for patients
and controls.

Medications
The type of medication that patients and controls are taking is important, particularly in studies recruiting patients with milder forms of
MDD whose impairment may be more subtle [48]. Research suggests
that neuropsychological impairment in MDD is not solely due to the
effects of antidepressant medication [5,49], because studies in unmedicated depressed patients have shown signicant differences in neuropsychological function compared with controls [50]. Some classes of
antidepressants, however, are more likely to cause neuropsychological
dysfunction, for instance, tricyclic antidepressants [51,52].

Categorization of patients by treatment outcome


A common way of analysing the relationship between change in
depressive symptomatology and change in neuropsychological function
was to compare remitters with non-remitters, or responders with nonresponders, at the end of the treatment period. The denition of remission, however, varies between studies, as does the mood rating scale
used. Furthermore, separating patients into remitters or non-remitters
could result in individuals who score close to the cut-off being misclassied [3]. In our opinion, measurement of improvement in depressive

symptomatology and improvement of neuropsychological function on


a continuum is preferable because this captures more of the variance in
the measures.

Time to follow up
The time between baseline and follow-up testing sessions varied
greatly between studies. Many of the studies involving neuropsychological testing were drug trials, and hence had 612 weeks between the
testing sessions. The importance of timing is crucial because not all
variables that remain the same over the follow-up sessions should automatically be classed as trait markers of MDD. It may be that these
variables simply take longer to return to normal than those classed as
state markers.

Subtype of MDD
The issue of clinical factors such as severity of MDD, inpatient status, presence of melancholia, comorbid anxiety and personality disorders, and number of episodes of depression should, if possible, be taken
into account and at least reported [48]. Certain aspects of these factors
may affect both the prole of neuropsychological dysfunction in MDD
and also the speed and completeness of response to treatment.
It is also likely that subtypes of MDD, such as bipolar or psychotic
depression, could have different neuropsychological proles during treatment. Table 1 lists studies in which bipolar or psychotically depressed
patients were included, but in some studies this information was not
provided. Only one study specically examined bipolar depression [8],
while remaining studies that included bipolar depressed patients did not
separate the analysis into subtypes, meaning that it cannot be determined
whether there are different neuropsychological changes over time between
unipolar and bipolar depression. Regarding psychotic depression, it is
known that this subtype is associated with a more widespread neuropsychological impairment [53], but we found no studies looking specically
at changes in neuropsychological performance during treatment in psychotic depression. Again, many studies in the review included depressed
patients with psychotic features, but did not conduct analyses to compare
neuropsychological changes in patients with non-psychotic features.

Age
Studies have suggested that the neuropsychological impairment associated with late-life MDD is more severe than in younger depressed
patients [54], particularly in the domains of psychomotor speed [42,43]
and in verbal memory [39]. An issue in late-life studies, however, is that
there may be an important difference between early- and late-onset
MDD. Most late-life studies in the present review include a mixture of
depressed patients with early- and late-onset MDD. Because of the possible different biological origin between early- and late-onset MDD [55],
this should be taken into account when examining neuropsychological
function in this group. Another important methodological factor is the
follow-up interval. Patients with late-life MDD may take longer to

NEUROPSYCHOLOGICAL CHANGE IN MDD

respond to treatment than younger patients with MDD [38], perhaps


resulting in changes in neuropsychological function taking longer.
Long follow-up intervals, however, could be confounded by age-related
decline and by progression of a number of patients to dementia.
This issue can of course be controlled for by using an age-matched
control group.

Discussion
After an extensive literature search, we identied 30
studies eligible for inclusion in this review. In adult
MDD samples, verbal measures of learning and memory and uency produced the most robust evidence of
sensitivity to clinical state, with improvement in these
tasks being signicantly related to improvement in
mood in a number of comprehensive studies. Why verbal measures appeared to be the most sensitive is
unclear, but it may be in part due to the relative ease of
administering verbal compared to non-verbal neuropsychological tasks. Pure measures of psychomotor speed
in the adult MDD samples showed some support of an
association with improvement in clinical state. It should
be noted that a major component of verbal uency, and
various other timed neuropsychological measures, is
psychomotor speed. Measures of executive functioning
and attention tended to remain impaired across treatment, suggesting a more trait-like feature of these
domains.
In late-life MDD the neuropsychological domain that
demonstrated the clearest association with treatment
response was psychomotor speed. Two studies that supported this view (using correlation and responders vs
non-responders as treatment outcomes) produced signicant evidence of improvement in psychomotor speed
with treatment response using the DSST [33], a pure
measure of psychomotor speed. In contrast, verbal memory and attention/executive functioning appeared to
remain impaired over time.
Given the ndings from younger adult and late-life
MDD samples, we recommend that a neuropsychological
testing battery including specic measures of VLM, verbal uency, and psychomotor speed be used in future
studies aiming to examine the relationship between mood
and neuropsychological functioning in MDD. Typical
measures of VLM used in this review were word listlearning tasks such as the Rey AuditoryVerbal Learning
Task, the California Verbal Learning Task, and the verbal
subtests of the Wechsler Memory ScaleRevised [33].
Inclusion of delayed recall and recognition components
allows for a more detailed examination of VLM, but in
severely depressed samples the original versions of these
tasks are likely to be poorly tolerated by some patients

1115

and subject to oor effects. Thus, shortening or modifying of the tasks may be necessary. The Controlled Oral
Word Association Task was the most common measure
of phonological and semantic (verbal) uency, while
design uency was measured with the Five-point Test
[33]. The DSST produced strong ndings in the late-life
MDD samples in the present review, and hence is our
recommendation for a pure psychomotor measure. In
late-life MDD studies it is important to have longer-term
follow up to allow for the possibility of prolonged treatment response.
This review also highlighted the variability of ndings
in neuropsychological studies of MDD and it was proposed that methodological issues were likely to be major
contributors to these inconsistencies. We suggest that
studies examining neuropsychological functioning across
treatment of MDD should include matched healthy controls (matched for age, gender, IQ and menstrual cycle),
take into account the medication status of patients and
the subtype of MDD they are diagnosed with, and directly
relate treatment response to changes in neuropsychological function. We believe that correlation of changes in
mood rating scale scores with changes in neuropsychological test scores is the optimal analysis, because it
eliminates the issue of categorical misclassication into
responders or remitters.
Future directions
The current review has presented evidence from studies
using traditional neuropsychological tasks. Increasing
attention, however, has been given to emotionally valenced
neuropsychological tasks in MDD, with one reviewed
article nding evidence of sensitivity to clinical state using
the emotional Stroop test [29]. Facial emotion recognition
tasks may also be useful objective markers of treatment
response. It has been found that depressed individuals are
more likely to classify ambiguous faces as negative [56],
consistent with psychological theories of MDD that
emphasize the role of negative biases in information processing [57]. Furthermore, studies have begun to clarify
the relationship between facial emotion recognition impairments and specic brain structures and neural pathways
involved in emotion perception [58]. Harmer provided preliminary evidence of negative biases in facial emotion
recognition in MDD normalizing with successful treatment [59], supporting a review that presented indirect support for facial expression perception as an objective
outcome measure for treatment studies in MDD [60].
Given the promising initial ndings, we believe that the
inclusion of a facial emotion recognition task [61] could
provide useful insights into neurobiological changes occurring during the treatment of MDD.

1116

K.M. DOUGLAS, R.J. PORTER

In addition to focusing our attention on alternative


measures that may indicate treatment response, it is also
important to continue to search for reasons why neuropsychological function is impaired in MDD. A possibility
is that severe or multiple episodes of MDD may result
in changes in neurobiology, giving rise to permanently
impaired neuropsychological function. Thus, long-term
description of the effects of multiple depressive episodes on
neuropsychological function would be of great interest.

Conclusion
The present review suggests that certain tests of neuropsychological function may be useful indicators of
treatment response in MDD. Being able to objectively
examine changes in brain function during treatment may
add to assessment of treatment response and potentially
aid clinicians in optimizing treatment. It may also add to
assessment of treatment efcacy in trials of treatments
for depression. Before this can occur, however, many
more methodologically sound, large-sample studies are
required to clarify the neuropsychological domains and
tests most sensitive to clinical state in MDD.
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