1106
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]
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)
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 MDD
Inpatient
MDD
Inpatient
P = 80
C = 62
Neu et al.
(2001) [30]
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
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]
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), as
deemed by
psychiatrist and
relatives.
Correlation
between HDRS
and neuropsyc.
HDRS and
MADRS scores
from baseline.
Treatment
outcome
measures
(Continued)
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 (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
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
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
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.
1111
1112
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
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.
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].
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
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
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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