DEPRESSION AND ANXIETY 30:515–527 (2013)

Review
COGNITIVE DEFICITS AND FUNCTIONAL OUTCOMES
IN MAJOR DEPRESSIVE DISORDER: DETERMINANTS,
SUBSTRATES, AND TREATMENT INTERVENTIONS
Roger S. McIntyre, MD, FRCPC,1,2,3,4 ∗ Danielle S. Cha, HBSc,3,4 Joanna K. Soczynska, HBSc,3,4
Hanna O. Woldeyohannes, HBSc,2 Laura Ashley Gallaugher, HBSc,2 Paul Kudlow, BSc, MD,2 Mohammad
Alsuwaidan, MD, MPH, FRCPC, Dip ABPN,3
and Anusha Baskaran, HBSc, MSc2,5

Background: Few reports have aimed to describe the mediational effect of cog-
nitive deficits on functional outcomes in major depressive disorder (MDD), and
relatively few interventions are demonstrated to mitigate cognitive deficits in
MDD. Methods: Studies enrolling subjects between the ages of 18–65 were se-
lected for review. Bibliographies from identified articles were reviewed to identify
additional original reports aligned with our objectives. Results: Cognitive deficits
in MDD are consistent, replicable, nonspecific, and clinically significant. The ag-
gregated estimated effect size of cognitive deficits in MDD is small to medium.
Pronounced deficits in executive function (≥1 SD below the normative mean) are
evident in ∼20–30% of individuals with MDD). Other replicated abnormalities
are in the domains of working memory, attention, and psychomotor processing
speed. Mediational studies indicate that cognitive deficits may account for the
largest percentage of variance with respect to the link between psychosocial dys-
function (notably workforce performance) and MDD. No conventional antide-
pressant has been sufficiently studied and/or demonstrated robust procognitive
effects in MDD. Conclusions: Cognitive deficits in MDD are a principal me-
diator of psychosocial impairment, notably workforce performance. The hazards
posed by cognitive deficits in MDD underscore the need to identify a consensus-
based neurocognitive battery for research and clinical purposes. Interventions
(pharmacological, behavioral, neuromodulatory) that engage multiple physio-
logical systems implicated in cognitive deficits hold promise to reduce, reverse,
and prevent cognitive deficits. Depression and Anxiety 30:515–527, 2013.

C 2013 Wiley Periodicals, Inc.

Key words: major depressive disorder; cognitive dysfunction; cognitive deficits;

dementia; duloxetine; vortioxetine; functional outcome

1 Institute
of Medical Science, University of Toronto, Toronto, Contract grant sponsor: Takeda Pharmaceutical Company, Ltd.
Canada ∗ Correspondence to: Roger S. McIntyre, MD, FRCPC, Mood Dis-
2 Mood Disorders Psychopharmacology Unit, University Health
orders Psychopharmacology Unit, University Health Network, Uni-
Network, Toronto, Canada versity of Toronto, 399 Bathurst Street, Toronto, ON, Canada M5T
3 Department of Psychiatry, University of Toronto, Toronto, 2S8. E-mail: roger.mcintyre@uhn.ca
Canada Received for publication 5 November 2012; Revised 4 January
4 Department of Pharmacology, University of Toronto, Toronto, 2013; Accepted 4 January 2013
Canada
5 Centre for Neuroscience Studies, Queen’s University,
DOI 10.1002/da.22063
Published online 6 May 2013 in Wiley Online Library
Kingston Canada (wileyonlinelibrary.com).


C 2013 Wiley Periodicals, Inc.
516 McIntyre et al.
INTRODUCTION
M ajor depressive disorder (MDD) is a multidimen-
sional mental disorder affecting approximately one in
seven individuals at some time in their life.[1] MDD is
associated with a high rate of nonrecovery and recur-
rence, with chronicity rates estimated at approximately
20%.[2] The estimated annual costs attributable to MDD
are approximately $83 billion, with indirect costs due to
decreased psychosocial function (notably workforce per-
formance) being a major contributor.[3] For example, it is
estimated that MDD is associated with an annual loss of
27.2 workdays per ill worker.[4] The human capital cost
attributable to MDD provides the impetus for identi-
fying determinants of functional impairment. Available
evidence indicates that cognitive dysfunction is a crit-
ical mediator of adverse psychosocial outcomes in this
population.[5–7]
The Diagnostic and Statistical Manual of Mental Dis-
orders – Fourth Edition – Text Revision (DSM-IV-TR)
identifies cognitive impairment (i.e., poor concentra-
tion or indecisiveness) as a criterion item of a major
depressive episode (MDE). Cognitive complaints dur-
ing the symptomatic and remitted phases are commonly
reported by individuals with MDD.[3, 4, 6, 8] When com-
pared to other severe mental disorders (e.g., schizophre-
nia, bipolar disorder), relatively fewer studies have
critically reviewed the affected cognitive domains and
estimated magnitude of cognitive impairment in MDD.
In addition, there have been fewer original reports
that have primarily aimed to parse out the neurobi-
ological substrate(s) of cognitive dysfunction in this
population, to determine the contribution of cognitive
dysfunction to psychosocial impairment, and to primar-
ily evaluate the procognitive effects of treatment (regard-
less of modality).
Replicated evidence indicates that cognitive dysfunc-
tion causes and maintains psychosocial impairment in
severe mental disorders.[5–7] Moreover, deficits in cog-
nitive function in adults under the age of 65 with MDD
cannot be sufficiently explained by age-related cogni-
tive changes. Available evidence suggests that cognitive
dysfunction is a critical determinant of functional out-
come in MDD.[7] It also remains to be determined if
the neurobiological substrate(s) that subserve cognitive
dysfunction in MDD are discrete and/or if they overlap
with substrate(s) implicated in other mental disorders.
Questions regarding which, if any, treatment modality is
more effective in mitigating cognitive deficits, enhancing
cognitive function and/or preventing their occurrence in
MDD remain unanswered. A general impression, albeit
based on relatively few empirical studies, is that cogni-
tive deficits are suboptimally treated with conventional
treatment approaches [e.g., selective serotonin reuptake
inhibitors (SSRIs)].[9–11]
The persistence of cognitive dysfunction in MDD
beyond resolution of the acute episode suggests that
it may represent a trait or a residual phenomenon in
many individuals. Moreover, it provides the impetus to
Depression and Anxiety
fundamentally re-think and perhaps redefine how “re-
mission” should be conceptualized.[6] Studies assessing
temporality of onset provide supporting evidence that
in some individuals, cognitive dysfunction may predate
the onset of the first MDE.[12] Cognitive dysfunction
can be disaggregated into two broad interrelated cate-
gories: (1) deficits in one or more cognitive domain(s)
or (2) cognitive bias: representing attentional alloca-
tion toward negatively valenced stimuli and/or aberrant
interpretation of social cues. It could be further sur-
mised that cognitive bias represents a trait characteristic
in individuals who are temperamentally predisposed to
MDD (e.g., neuroticism). The preponderance of evi-
dence indicates that cognitive deficits are a consequence
and/or residual phenomenon of MDD and in relatively
fewer cases may be an antecedent to MDD. (The no-
tion that cognitive deficits predate the onset of MDD
is more frequently reported in older individuals with
MDD).
Relatively few studies have evaluated the effect
of conventional antidepressants on cognitive perfor-
mance in nongeriatric, adult MDD samples. Selective
serotonin reuptake inhibitors (SSRIs), selective nore-
pinephrine inhibitors (SNRIs), dopamine modulators
(bupropion), and norepinephrine inhibitors (reboxe-
tine) have been reported to improve cognitive per-
formance in adults with MDD.[13–18] There is also
a paucity of evidence comparing the effects of dif-
ferent classes of antidepressants.[16–18] Questions per-
taining to the degree to which the improvement in
cognitive deficits can be dissociated from the ef-
fect of other MDD psychopathology domains (e.g.,
chronicity, subtype of MDD, number and duration of
MDEs) and/or comorbidities have been insufficiently
addressed.
The overarching aim of this review is to describe the
role of cognitive dysfunction as a determinant of func-
tional outcome in MDD. Toward this aim, we succinctly
review (1) cognitive deficits and their determinants in
adults with MDD 65 years old or younger (i.e., 18–65
years) and (2) the effect of treatment on cognitive per-
formance. The secondary objectives of this review are to
identify underlying substrate(s) that subserve cognitive
deficits and to propose treatment approaches that pri-
marily aim to mitigate, reverse, and prevent deficits in
cognitive function.
METHOD
We conducted a review of computerized databases (i.e., PubMed,
Google Scholar) from 1980 to 2012. “MDD” was cross-referenced
with the following terms: cognitive dysfunction, cognitive deficits, de-
mentia, and functional outcome. Studies enrolling subjects between
the ages of 18–65 were primarily selected for review: select studies in
late life depression in the absence of studies in adults 65 years of age or
less were also reviewed were also reviewed. Bibliographies from iden-
tified articles were also reviewed in order to identify any other original
reports that were aligned with the objectives of this paper.
 Review: Cognitive Deficits and Functional Outcomes in MDD 517

RESULTS TABLE 1. Common neurocognitive tests

NEUROCOGNITIVE TESTS Cognitive domain Neurocognitive tests

Table 1 contains a list of conventional instru- Executive function • Wisconsin Card Sorting Test (WCST)
ments and batteries frequently administered for as- (concept • Trail-Making Test Part B (TMT B)
sessing cognitive function. The available tests measure formation, • Stroop Colour-Word Interference Test
intellectual functioning, working memory, verbal learn- abstraction, set (SCWT)
ing and memory, attention and information processing shifting, set • Categories Test
speed, executive function, psychomotor performance, maintenance, • Block Design (WAIS-R)
planning, • Picture Completion (WAIS-R)
and global cognitive function. None of the foregoing
self-monitoring, • Concept Shifting Task (CST)
cognitive measures have been specifically developed to divided attention) • Tower of London (TOL; CANTAB)
evaluate cognitive performance and/or its functional im- • Stockings of Cambridge (SOC; CANTAB)
plications in the workforce. • Intra/Extradimensional Shift Test
(CANTAB; IED)
• Spatial Span (SSP; CANTAB)
COGNITIVE DEFICITS IN MDD • Ruff Figural Fluency Test (RFFT)
The interpretation of study outcomes as they pertain • Verbal Fluency–Letter Fluency & Category
to cognitive deficits in MDD begins with a review of Fluency
methodological factors that may affect the interpreta- • Controlled Oral Word Association Test
(COWAT)
tion of the data. First, available studies are often inclu-
• The Delis-Kaplan Executive Function
sive of heterogeneous sample compositions that have in- System (D-KEFS)
cluded mixed ages, disparate definitions of MDD, and Attention and • Digit Symbol Substitution Test (DSST;
illness characteristics (e.g., age at onset, duration, num- processing speed WAIS-R)
ber of episodes, depression subtype, presence or absence • Digit Span Forwards and Backwards
of psychotic features) as well as treatments. Additionally, (WAIS-R)
the co-occurrence of medical and/or psychiatric condi- • Continuous Performance Task (CPT)
tions has not always been controlled. The relevance of • Reaction Time (RTI; CANTAB)
this latter observation is underscored by evidence in- • Choice Reaction Time (CRT; CANTAB)
dicating that comorbid conditions in MDD may exert • Simple Reaction Time (SRT; CANTAB)
• Trail-Making Test Part A (TMT A)
direct effects on cognitive performance (e.g., attention
• Paced Auditory Serial Addition Test
deficit/hyperactivity disorder, obesity).[19, 20] For exam- (PASAT)
ples of determinants of cognitive deficits in MDD, see • Serial Sevens Subtraction Test (SSST)
Table 2. Working memory • Arithmetic (WAIS-R)
Most studies evaluating cognitive dysfunction in • Digit Span Forwards and Backwards
MDD have enrolled symptomatic and treated individ- (WAIS-R)
uals whereas relatively fewer studies enrolled “asymp- • Delayed Recognition Span Test (DRST)
tomatic” and/or individuals not receiving medication. • Spatial Working Memory (SWM;
Most studies have evaluated cognitive function follow- CANTAB)
ing the onset of MDD. However, there is little docu- • Letter-Number Sequencing (LNS; WMS-R)
• Logical Memory (WMS-R)
mentation reporting on cognitive performance prior to
• n-Back Test
the onset of an index MDE. A separate understudied is- Verbal learning and • California Verbal Learning Test (CVLT)
sue relates to the impact of early childhood adversity on memory • Rey Auditory Verbal Learning Test
cognitive measures in adult samples with MDD and its (RAVLT)
moderational effect.[21] • Rivermead Behavioral Memory Test
A notable factor affecting interpretation of study re- (RBMT)
sults is the heterogeneity of neurocognitive tests and bat- • Hopkins Verbal Learning Test Revised
teries. Most available studies include tests that evaluate (HVLT-R)
performance across several principal cognitive domains • Logical Memory (WMS-R)
(see Table 1). There is, however, no accepted “gold • Verbal Paired Associates (VPA; WMS-R)
• Visual Verbal Learning Test (VVLT)
standard” psychometric of cognitive function in MDD
• Digit Span Forwards and Backwards
that has been embraced by the research/clinical com- (WAIS-R)
munity. In contradistinction, there have been efforts to • Luria Verbal Learning Test (LVLT)
agree upon a common set of tests for individuals with • Serial Sevens Subtraction Test (SSST)
primary psychotic disorders for both descriptive and • Verbal Recognition Memory Test (VRM;
interventional research [e.g., measurement and treat- CANTAB)
ment in research to improve cognition in schizophrenia Visual learning and • Visual Reproduction (WMS-R)
(MATRICS)]. In the clinical setting, subjective memory • Benton Visual Retention Test (VRT)
complaints of cognitive deficits are common.[22–24] • Benton Visual Form Discrimination (VFD)
Notwithstanding the ubiquity of cognitive complaints,
Depression and Anxiety
518 McIntyre et al.

TABLE 1. Continued TABLE 2. Determinants of cognitive deficits in major

depressive disorder (MDD)
Cognitive domain Neurocognitive tests
Age[86]
• Rey-Osterrieth Complex Figure Test Age at onset[87]
(ROCF) Educational attainment[88]
• Kimura’s Recurring Figures Test (RFT) Baseline depression severity[89]
• Visual Verbal Learning Test (VVLT) MDD subtype[90]
• Pattern Recognition Memory (PRM; Symptomatic status (i.e., remission vs. nonremission)[14, 30, 91]
CANTAB) Psychiatric comorbidity[92]
• Spatial Recognition Memory (SRM; Medical comorbidity[93, 94]
CANTAB) Illness duration[9]
• Delayed Matching to Sample (DMS; Episode frequency[32]
CANTAB) Treatment[66]
• Paired Associates Learning (PAL; Childhood adversity[95, 96]
CANTAB)
• Matching Familiar Figures Test 2
(MFFT-20)
Language and verbal • Controlled Oral Word Association Test the congruence between subjectively reported and ob-
comprehension (COWAT) jectively measured cognitive deficits is not consistent in
• Verbal Fluency–Category Fluency & Letter MDD.[25]
Fluency
A common convention among extant studies is the
• Similarities (WAIS-R)
• Vocabulary (WAIS-R)
reporting and comparing of group means rather than
• Information (WAIS-R) an emphasis on individuals who fall below a pre-
• Comprehension (WAIS-R) specified cut score for cognitive dysfunction [i.e., 1–
• Token Test 2 standard deviations (SD) below the norm].[26] This
Visuospatial/ • Judgement of Line Orientation (JOLO) convention may inadvertently decrease the “assay sensi-
perceptual • Benton Visual Form Discrimination (VFD) tivity” and not provide a sufficient estimate of the mag-
processing • Block Design (WAIS-R) nitude of deficits, and/or the functional implications, in
• Visuospatial Span Forwards and Backwards MDD. Moreover, the use of mean scores in parametric
(WMS-R) statistics assumes normal distribution of the dependent
Brief mental status • Mini Mental State Exam (MMSE)
variable. As the mean scores influence extreme values,
General intelligence • Raven’s Progressive Matrices
• Wechsler Adult Intelligence Scale—Revised
the emphasis on mean scores rather than the SD from
(WAIS-R) the normative population mean could underestimate the
• National Adult Reading Test (NART) magnitude of deficits that affect a subgroup of individu-
• Wechsler Test of Adult Reading (WTAR) als with MDD.[26] For example, individuals with MDD
• Test of Nonverbal Intelligence-3 (TONI-3) fall, on average, 0.5–1 SD below the normal population
Cognitive battery • Cambridge Neuropsychological Test mean.[14]
Automated Battery (CANTAB) Notwithstanding it is reported that approximately 25–
• Wechsler Memory Scale—Revised 50% of patients with MDD exhibit deficits that are
(WMS-R) more than 1 SD below the mean on at least one cog-
• Wechsler Adult Intelligence Scale—Revised
nitive domain and as many as 48% score more than 2
(WAIS-R)
• Victoria Symptom Validity Test (VSVT)
SD below the mean.[26] A summary statement regarding
• California Computerised Assessment cognitive deficits in MDD is that cognitive deficits are
Package (CalCAP) consistent, replicable, nonspecific, clinically significant,
• CNS Vital Signs and of small to medium in effect size. The most repli-
• Massachusetts General Hospital Cognitive cated cognitive deficits are in the domains of executive
and Physical Functioning Questionnaire function, working memory, attention, as well as general
(CPFQ) and psychomotor processing speed (e.g., sensorimotor,
• The Delis-Kaplan Executive Function cognitive).[27] A limitation of the approach that defines
System (D-KEFS) deficits based on deviations from the standard popula-
Psychomotor • Finger Tapping
tion means is that it is not inclusive of individuals who
performance • Grooved Pegboard Test
• Purdue Pegs
remain above the mean, possibly due to cognitive re-
Decision making • The Go/No-go Association Task (GNAT; serve (e.g., education, occupation, intelligence),[28] but
and response CANTAB) report deterioration compared with baseline. It could be
control • Information Sampling Task (IST; hypothesized that these “uncaptured” deficits likewise
CANTAB) contribute significantly to relative functional decline in
• Cambridge Gambling Task (CGT; these individuals.
CANTAB) The conventional assumption has been that cognitive
Induction • Big/Little Circle (BLC; CANTAB) deficits in MDD are a consequence or a residual fea-
ture of an acute MDE. For example, individuals with
Depression and Anxiety
 Review: Cognitive Deficits and Functional Outcomes in MDD
remitted MDD often exhibit persisting cognitive deficits
in measures of attention, executive function, and verbal
memory.[29, 30] There have been relatively few studies
evaluating the temporality of onset, wherein cognitive
deficits are documented prior to the onset of MDD.
Notwithstanding the paucity of data, a longitudinal,
population-based study has reported a significant associ-
ation between episodic memory function and emergent
depressive symptoms during a 2-year follow-up.[31]
A separate study that broadly aimed to identify pre-
morbid markers of depression in a population-based
sample of nondepressed individuals (N = 708) evalu-
ated prospectively over a 3-year period reported that
female gender, lower educational attainment, low so-
cial support, financial strain, and poor episodic memory
(but not verbal fluency, psychomotor speed, or men-
tal speed) were associated with an increased risk of
depression.[12] These results suggest that hippocampal-
dependent memory may be abnormal prior to the clinical
presentation of depression.[12] The persistence of cog-
nitive deficits in asymptomatic individuals as well as the
identification of cognitive deficits prior to the presence
of symptomatic depression indicates that in many in-
dividuals, cognitive deficits can be conceptualized as a
core deficit rather than an epiphenomenon of a MDE
(i.e., secondary to diminished initiative and effortful
processing).
Replicated evidence indicates that episode frequency
and illness duration are significantly associated with
the presence of cognitive deficits.[32, 33] For example,
a large study (N = 8,229) of outpatients with MDD
reported that declarative memory (measured with the
delayed paragraph recall index from the Wechsler
Memory Scale—Revised), a surrogate marker of hip-
pocampal function, decreases approximately 2–3% with
each MDE, up to four episodes.[32] This decrement
in memory parallels results from morphometric stud-
ies that have documented volumetric reduction in the
hippocampus in MDD with a more pronounced de-
crease observed during the first several episodes.[32, 34]
Current illness severity was the major determinant of
performance, as opposed to the intensity of their pre-
vious depressive history (i.e., the number and length
of past episodes). However, following clinical response
at the second visit, the length of previous depres-
sive history became more significant than current
symptoms.[32, 34]
Not all reports identify episode frequency as a de-
terminant of cognitive deficit. For example, a meta-
analysis of cognitive deficits in first episode MDD
reported small-to-moderate effect size decreases in psy-
chomotor speed, attention, visual and learning memory
as well as all aspects of executive function.[27] The pres-
ence of cognitive deficits during the first MDE as part
of MDD indicates that cognitive performance repre-
sents a target for early identification, measurement, and
intervention.[27, 35]
Taken together, there are multiple determinants of
cognitive outcome in MDD: heterogeneity of sample
519
composition, treatment regimens, patterns of comorbid-
ity, definitions of depression and cognition measures, as
well as insufficient adjustment for early childhood ad-
versity and colinearity, are major methodological lim-
itations. Notwithstanding cognitive deficits in MDD
are a consistent observation exhibiting trait, state, and
progressive features.
COGNITIVE DEFICITS IN MDD: LINK TO
FUNCTIONAL OUTCOME
Results from the Global Alliance and Chronic Disease
Report extend and replicate the observation that MDD
is associated with the highest level of disability-adjusted
life years among all mental, neurological, and substance
use disorders.[36] A significant component of the overall
disability and cost associated with depression relates to
impaired workplace performance.[4]
The effect of neurocognitive deficits as a mediator
of disability in individuals with MDD has been insuffi-
ciently studied. Jaeger et al. reported that measures of at-
tention, ideational fluency, nonverbal (i.e., visuo-spatial)
and learning domains were highly associated with dis-
ability 6 months following hospitalization for a MDE in
a relatively small cohort (N = 48) of adults with MDD.[5]
Naismith et al. sought to determine whether sub-
jective and/or objective measures of cognitive per-
formance were related to measures of psychomotor
performance.[25] A small sample (N = 21) of adults
treated for MDD exhibited a moderate relationship
between objectively measured psychomotor speed and
physical disability.[25] Functional disability was mod-
erately correlated to objective measures of memory
retention.[25] Measures of mental health disability (i.e.,
Brief Disability Questionnaire Mental Health and SF-12
Well-Being) were not associated with any neuropsycho-
logical measure.[25] These results replicate and extend
observations of an association between cognitive deficits
and functional outcomes in a separate small sample of
adults with MDD as well as individuals with late-life
MDD.[29, 37, 38]
Buist-Bouwman et al. conducted a mediational anal-
ysis of the European Study of the Epidemiology of
Mental Disorders (ESEMeD), a cross-sectional sur-
vey representative of the adult population in Belgium,
France, Germany, Italy, Netherlands, and Spain
(N = 21,425, age ≥ 18).[7] The mediating effects of
six activity limitations (Mobility, Self Care, Cogni-
tion/Concentration/Attention/Memory, Social Interac-
tion, Discrimination, Embarrassment) articulated in the
WHO International Classification of Functioning, Dis-
ability, and Health were evaluated.[7] Cognition and em-
barrassment were the only determinants significantly
associated with both MDEs and work functioning.[7]
Moreover, cognition and embarrassment accounted for
approximately half of the association between a MDE
and work loss, underscoring the salience of cognitive
function in mediating and reducing role functioning in
MDEs.[7]
Depression and Anxiety
520 McIntyre et al.
Taken together, cognitive deficits in MDD are not
only characterized by poor performance on objective and
subjective measures, but also appear to be a principal me-
diator of functional impairment.[39, 40] This observation
underscores the prioritization of cognitive deficits in the
evaluation and management of individuals with MDD.
COGNITIVE DYSFUNCTION IN MDD:
NEUROBIOLOGICAL SUBSTRATE
Contemporary models of disease pathoetiology in
MDD have been extensively reviewed elsewhere.[41]
Progress in molecular and cellular biology as well as
results from neuroimaging investigations have served
to refine the hypothesis that disparate domains of
psychopathology in MDD are subserved by abnor-
malities in the structure, function, and chemical
composition of fronto-subcortical circuitry.[42, 43] A pre-
liminary study also suggests that brain activation pat-
terns suggestive of functional disconnectivity in MDD
may be different in individuals who are on long-term sick
leave when compared with those who are able to main-
tain workplace performance.[44] Moreover, several nodal
structures (e.g., hippocampus, amygdala, anterior cin-
gulate cortex) are susceptible to volumetric/functional
changes as a consequence of illness duration, episode
frequency, and severity.[34, 43, 45] The neurochemical ab-
normalities that are well documented in individuals with
MDD can be conceptualized as a consequence of aber-
rant cellular functioning within the implicated neural
circuits.[46–48] For example, disturbances in monoamine
systems, notably catecholamine systems, have been doc-
umented to play a role in attentional and executive
function deficits.[49]
A derivative of this hypothesis is that the neurobiolog-
ical correlates (i.e., neural circuits) of cognitive function
and deficits, overlap with those implicated in other com-
ponents of MDD.[47] The most replicated volumetric
abnormality in MDD is bilateral hippocampal reduction,
which is a consequence of loss of neuropil, decreased
dendritic density, and reduced neuronal soma size.[34, 50]
Hypofrontality of the prefrontal cortex and overactivity
of the anterior cingulate cortex are hypothesized to be
the correlate of a functional disconnection between cor-
tical and subcortical structures.[43, 51] These alterations
may mediate deficits in measures of executive function,
attention, learning and memory, as well as information
processing speed.
The mediators of aberrant neural circuitry, structure
and function are hypothesized to include alterations
in regulatory–counterregulatory hormone balance
(i.e., glucocorticoid-signaling abnormalities, insulin
resistance), immunoinflammatory activation, neu-
rotrophins [e.g., Brain-Derived Neurotrophic Factor
(BDNF)], and oxidative stress.[46, 52–54] A separate, and
possibly related, observation is that recurrent MDD
is associated with an increased hazard for Alzheimer’s
disease (AD).[44] For example, results from postmortem
studies indicate that a history of MDD is associated
Depression and Anxiety
with greater neuritic plaque density in neuropatho-
logically confirmed Alzheimer’s brain.[55] Moreover,
cognitively intact adults with MDD manifest lower
cerebrospinal fluid concentration of beta-amyloid,
providing indirect evidence for parenchymal deposition
of beta-amyloid-42.[56]
A bidirectional relationship between MDD and
metabolic disorders has been amply documented.[57] Ac-
cumulating evidence supports the hypothesis that al-
terations in insulin signaling may be relevant to neu-
rocognitive decline in subpopulations of individuals with
MDD. For example, insulin resistance and diabetes mel-
litus type 2 are associated with cognitive deficits in
younger adults as well as those with mild cognitive
impairment (MCI) and AD.[58] An imbalance between
insulin and counterregulatory neurohormonal systems
(i.e., glucocorticoids) may alter pro-apoptotic intracellu-
lar signaling cascades thereby resulting in neuronal/glial
loss and neurocognitive decline.[59, 60]
The default mode network (DMN), a proposed net-
work of neural circuits that connects cortical and subcor-
tical structures, may be relevant to cognitive function.[61]
The DMN comprises several nodal structures including
the ventral–medial–prefrontal cortex, posterior cingu-
late/retrosplenial cortex, and bilateral inferior parietal
lobe.[61] The DMN is usually more active during the
“resting state” than it is during a cognitive, emotional,
and/or motor task.[62] Abnormalities in the DMN have
been implicated in pathological disease states of which
cognitive deficits are a defining feature (e.g., AD).[63]
An integrated translational research report indicated that
abnormalities in insulin resistance are accompanied by
disturbances in the DMN in individuals at risk for AD.
Moreover, modafinil, an agent with established procog-
nitive effects by enhancing catecholamine neurotrans-
mission, augments deactivation in the major nodal struc-
tures of the DMN.[61]
In summary, the pathoetiological model in MDD
posits structural and functional disturbances in inter-
connected neural circuits and distributed networks. The
substrates that subserve cognitive performance in MDD
have overlapping and discrete components from the
substrates subserving affective processing; refining the
model subserving domains of psychopathology in MDD
hold promise to inform interventional strategies for cog-
nitive deficits in MDD.
THE EFFECT OF INTERVENTION ON
COGNITIVE DEFICITS IN MDD
All commercially available and approved conventional
antidepressants augment central indolamine and/or cat-
echolamine neurotransmission.[64, 65] This pharmacody-
namic profile provides the basis for hypothesizing that
antidepressants, in addition to mitigating both the mood
and vegetative symptoms of an MDE, would also be ex-
pected to ameliorate cognitive deficits. There are, how-
ever, relatively few studies that have primarily aimed
to evaluate the effect of conventional antidepressants
 Review: Cognitive Deficits and Functional Outcomes in MDD
on cognitive performance in nongeriatric, adult MDD
samples.[13–15] Available evidence indicates that SSRIs,
SNRIs, dopamine modulators (bupropion), and nore-
pinephrine inhibitors (reboxetine) improve cognitive
performance in adults with MDD.[16–18] There are also
relatively few studies that have compared the cognitive
effects of different classes of antidepressants on cogni-
tive function.[16–18] Insufficiently answered questions in-
clude the degree to which the improvement in cognitive
deficits can be dissociated from the effect on other MDD
psychopathology domains.
Herrera-Guzman et al. reported on the cognitive ef-
fects of escitalopram and duloxetine in adults (aged 20–
50) with MDD.[16] They observed that both treatments
improved working memory, attention, and executive
function as well as mental processing speed and mo-
tor performance.[16, 66] Duloxetine was superior to es-
citalopram on episodic and working memory whereas
no significant differences between the antidepressants
were observed on measures of attention and executive
function.[16, 66]
Raskin et al. sought to determine the effect of dulox-
etine versus placebo on several measures of cognitive
performance.[10] A study in older adults (62–90 years of
age) is reviewed as, to our knowledge, it is the only study
that primarily aimed to evaluate a conventional antide-
pressant’s ability to mitigate cognitive deficits in a cohort
of adults with MDD.[10] They reported that when com-
pared to placebo, 8 weeks of treatment with duloxetine
significantly improved the cognitive composite score.[10]
The improvement in the duloxetine-treated group was
largely accounted for by improvement in measures of
verbal learning and recall with trending between-group
differences noted on attention [i.e., Digit Symbol Sub-
stitution Test (DSST)], visual attention and executive
function (i.e., Two-Digit Cancellation Test), and work-
ing memory/executive function (i.e., Letter-Number Se-
quencing Test).[10] Path analyses showed that for the
improvement of the cognitive composite score, there
was a 90.9% direct effect and 90.1% indirect effect
through improvement in a Geriatric Depression Scale
Total Score.[10]
Vortioxetine (Lu AA21004) is a novel multi-modal
antidepressant that exhibits 5-HT3 and 5-HT7 re-
ceptor antagonism, 5-HT1B receptor partial agonism,
5-HT1A receptor agonism, and inhibition of the 5-HT
transporter. In addition to its effect on indolamine sig-
naling, vortioxetine also increased central neurotrans-
mission of noradrenaline, dopamine, acetylcholine, and
histamine.[67] Vortioxetine has demonstrated antide-
pressant efficacy in MDD in adult and elderly pop-
ulations as well as in adults with generalized anxiety
disorder.[68, 69] In addition to antidepressant proper-
ties, vortioxetine has demonstrated cognitive-enhancing
properties in animal and human studies.[70] For ex-
ample, vortioxetine showed statistically significant im-
provement on acquisition and delayed recall (as mea-
sured by the Rey Auditory Verbal Learning Test), as
well as information processing speed (as measured by
521
the DSST) in a group of elderly (N = 453) nonde-
mented individuals with MDD.[68] In this study, duloxe-
tine, the active control, also demonstrated improvement
on RAVLT, but not DSST.[68] A path analysis concluded
that 83% of the improvement on DSST with vortioxe-
tine was a direct effect (duloxetine 26%), while the direct
effect on acquisition and delayed recall (i.e., RAVLT)
was 71% and 72%, respectively (for duloxetine 65%
and 66%, respectively).[68] The beneficial effects of vor-
tioxetine in this study on cognitive performance were a
secondary outcome, providing an empirical basis for
evaluating the effect of this agent on cognition and con-
sequently functional outcomes as a primary outcome in
younger adults with MDD.[68]
Notwithstanding the paucity of studies, a signal that
emerges from the foregoing studies is that treatment in-
terventions that engage multiple neurochemical systems
simultaneously may be more likely to improve cogni-
tive performance when compared to interventions that
principally target a single system (e.g., SSRIs). In keep-
ing with this view, it is not uncommon for practition-
ers to coprescribe mechanistically diverse agents (e.g.,
modafinil, psychostimulants) and/or suggest behavioral
interventions (e.g., aerobic exercise) in addition to con-
ventional antidepressant treatment with an aim to pri-
marily target the cognitive domain. Hitherto, no Food
and Drug Administration (FDA) approved agent for de-
pression has been purposefully evaluated to mitigate cog-
nitive deficits and improve psychosocial functioning in
MDD.
DISCUSSION
Several observations emanate from the synthesis of the
data reviewed herein.[3, 36, 71, 72] The functional impair-
ments (notably workforce impairment) associated with
MDD disproportionately account for the overall costs
attributable to MDD.[3, 73] This observation provides
the basis for elucidating determinants of psychosocial
impairment in MDD.[3, 73] A global shift in the work-
force away from primary industry toward a skilled hu-
man capital economy will only amplify the importance of
diseases/disorders of the central nervous system (CNS)
and their actuarial costs.[3, 72, 74]
Cognitive deficts in MDD are prevalent and may
represent a core dimension of psychopathology in
MDD.[31, 32, 75] Cognitive deficits are often a persist-
ing abnormality in individuals with MDD and in some
cases may predate the onset of clinically significant
depressive symptoms.[12, 27] The observation that cog-
nitive deficits mediate psychosocial impairment (i.e.,
accounting for a significant percentage of variance) and
intervention.[7, 26, 74] When compared with severe men-
tal disorders (e.g., schizophrenia, bipolar disorder), rela-
tively less emphasis has been given to the hazards posed
by cognitive deficits in MDD. Along with the method-
ological limitations that affect inferences and interpre-
tations that may be drawn from the extant data per-
taining to cognitive deficits in MDD, there is no “gold
Depression and Anxiety
522 McIntyre et al.

TABLE 3. Effects of pharmacological treatment on cognitive deficits in major depressive disorder

Cognitive
Author Year Population Treatment Cognitive tests deficits/improvements

Ferguson et al. 2003 74 MDD (age range = Reboxetine (8–10 mg/day; SRT, Digit Vigilance, Reboxetine significantly
18–65) N = 25) CRT, Numeric WM, improved sustained
Paroxetine (20–40 Word Recognition, and attention and speed of
mg/day; N = 23) Critical Flicker cognitive functioning
Placebo (N = 26) Frequency compared with baseline
No significant changes or
trends in this direction
were observed in
individuals receiving
either paroxetine or
placebo
Constant et al. 2005 20 MDD (mean age = Sertraline (50–75 mg/day) Phasic Alertness Task, MDDs had psychomotor
47.67) Classic SCWT, and the slowing associated with
26 healthy controls (mean Supraliminal and attentional and
age = 48.85) Subliminal Emotional executive disturbance
Stroop test Following first weeks of
treatment, a beneficial
effect on psychomotor
slowing on attentional
and executive functions
was observed
Gualtieri et al. 2006 38 drug-free MDD (mean Citalopram (N = 1) CNS Vital Signs Untreated MDDs had
age = 38.11, SD = 9.95) Fluoxetine (N = 3) global
31 MDD antidepressant Escitalopram (N = 8) neuropsychological
monotherapy Paroxetine (N = 3) impairment.
responders (mean age = Mirtazapine (N = 1) Successfully treated
43.55, SD = 10.68) Trazodone (N = 1) MDD`s performance
69 healthy controls (mean Venlafaxine (N = 5) improved, but not
age = 41.30, SD = Bupropion (N = 6) normalized
11.40) Sertraline (N = 3) Specific
depression-related
deficits were observed
in executive function
and processing speed,
but not in memory,
psychomotor speed, or
reaction time
Gualtieri et al. 2007 81 MDD (mean age = Bupropion (N = 27) CNS Vital Signs SSRI group scored
43.85) Venlafaxine (N = 27) significantly below
27 healthy controls (mean SSRI (N = 27) controls in tests of
age = 43.85) psychomotor speed,
cognitive flexibility, and
reaction time
Venlafaxine group scored
worse than controls in
reaction time
Bupropion group did not
differ from controls in
any of the cognitive
domains
Raskin et al. 2007 311 MDD Duloxetine (60 mg/day; N Verbal Learning and Duloxetine demonstrated
Duloxetine (N = 207; = 207) Recall Test, DSST, significantly greater
mean age = 72.6, SD = Placebo (N = 104) Cancellation Test, LNS improvement versus
5.7) placebo. MDD with
Placebo (N = 104; mean duloxetine treatment
age = 73.3, SD = 5.7) improved verbal
learning and memory

Depression and Anxiety

 Review: Cognitive Deficits and Functional Outcomes in MDD 523

TABLE 3. Continued

Cognitive
Author Year Population Treatment Cognitive tests deficits/improvements

Herrera-Guzman 2010 73 MDD Escitalopram (10 mg/day; Vocabulary, Digit Span SSRI and SNRI
et al. SSRI (N = 36; mean age N = 36) and SWM, Rapid treatments both
= 32.91, SD = 8.73) Duloxetine (60 mg/day; N Visual Information improved WM,
SNRI (N = 37; mean age = 37) Processing, DMS, attention, and all
= 33.21, SD = 8.61) SCWT, IED, SOC executive functions.
37 healthy controls (mean However, MDD`s
age = 33.05, SD = 8.04) cognitive function did
not improve enough to
reach levels of control
subjects
Herrera-Guzman 2010 73 MDD Escitalopram (10 mg/day; Vocabulary, Digit Span, SSRI and SNRI
et al. SSRI (N = 36; mean age N = 36) AVLT, PRM, PAL, treatments both
= 32.91, SD = 8.73) Duloxetine (60 mg/day; N DMS, SRM, RTI, improved episodic
SNRI (N = 37; mean age = 37) SCWT memory and, to a lesser
= 33.21, SD = 8.61) extent, WM, mental
37 healthy controls (mean processing speed and
age = 33.05, SD = 8.04) motor performance.
SNRI was superior to
SSRI at improving
episodic memory and
WM
Herrera-Guzman 2010 73 MDD Escitalopram (10 mg/day; Vocabulary, SWM, MDDs in remission
et al. SSRI (N = 36; mean age N = 36) RAVLT, PAL, SOC, showed deficits in verbal
= 32.91, SD = 8.73) Duloxetine (60 mg/day; N Rapid Visual and visual episodic
SNRI (N = 37; mean age = 37) Information Processing memory, sustained
= 33.21, SD = 8.61) attention, mnemonic
37 healthy controls (mean and strategic aspects of
age = 33.05, SD = 8.04) WM, and planning.
MDDs in recovery
showed the same
neuropsychological
deficit pattern. MDDs
treated with SSRI
showed more
impairment in episodic
visual and verbal
memory than those
treated with SNRI
Hinkelmann et 2012 N = 52 MDD with SSRI Baseline RAVLT, Digit Span F and MDD performed worse
al. treatment and add-on Escitalopram (10–20 B, ROCF, Cancellation compared with healthy
treatment modulating mg/day; N = 52) test, TMT A and B controls (Digit Span
the mineralocorticoid Add-on treatment Forward, ROCF,
receptor MR-agonist Cancellation Test),
N = 50 healthy subjects fludrocortisone (0.2 indicating ongoing
mg/day; N = 19) relative cognitive
MR-antagonist deficits in these
spironolactone (100 domains. No differences
mg/day; N = 22) between the three
Placebo (N = 11) treatment groups were
observed over time

standard” to measure cognitive deficits in research
settings and/or to succinctly and comprehensively mea-
sure cognitive deficits in the clinical ecosystem. More-
over, as interest in patient-reported outcomes in psy-
chiatric and medical disorders increases, there will be
a need to identify not only objective, but also sub-
jective measures of cognitive functions that are valid,
reliable, and have utility for personalizing treatment
interventions.[76]
MDD is a heterogeneous phenotype in phenomenol-
ogy and pathoetiology. There is no single disease model
that will sufficiently explain the panoply of abnormal-
ities observed across disparate populations. Admittedly
complex, a conceptual framework of disease modeling in

Depression and Anxiety

524 McIntyre et al.
MDD that would be comprehensive and coherent would
posit that there are multiple (i.e., hundreds, if not thou-
sands) disease pathways in MDD. Succinct neurobio-
logical substrate(s) of neurocognitive dysfunction is not
currently available. Notwithstanding available evidence
implicates altered cellular, synaptic, and circuitry abnor-
malities in MDD manifesting as disturbances in central
neurotransmitter signaling.[46, 52–54, 77]
Robust therapeutic interventions specifically tar-
geting cognitive deficits in MDD are not currently
available, largely due to insufficient empirical obser-
vation. Notwithstanding available evidence indicates
that targeting multiple monoamine systems mitigates
cognitive deficits independent of its effect on other
depressive symptoms.[10, 16, 66] The complex pathoeti-
ology of cognitive deficits provides the basis for hy-
pothesizing that interventions capable of engaging
multiple physiological systems may be differentially ef-
fective for this domain of psychopathology. Moreover,
it remains a testable hypothesis that mitigating cog-
nitive deficits in MDD would result in an improve-
ment in overall psychosocial performance, notably in the
workforce.
Refining disease models in MDD will provide a plat-
form for identifying genuinely novel, pharmacological
treatment approaches to treat, reverse, and prevent cog-
nitive deficits in MDD (Table 3). Extrapolating from re-
sults reported in schizophrenia and bipolar disorder, it is
reasonable to expect that some adults with MDD would
be candidates for cognitive remediation and neurore-
habilitative activities/endeavors.[78–82] Moreover, novel
neuromodulatory approaches [e.g., repetitive Transcra-
nial Magnetic Stimulation (rTMS)], complementary al-
ternative medicine (e.g., N-acetyl-cysteine), and behav-
ioral interventions (e.g., aerobic exercise) may also have
a place in the armamentarium against cognitive deficits
in MDD beyond resolution of the acute episode.[13, 83–85]
Acknowledgments. This review was sponsored by
the Takeda Pharmaceutical Company, Ltd., as part of
a joint clinical development program with H. Lund-
beck A/S. Dr. McIntyre drafted and reviewed successive
versions of the manuscript. Editorial support, including
styling and editing for journal submission, was provided
by The Medicine Group, New Hope, Pennsylvania.
Conflict of interest. The authors have no conflicts of
interest. Joanna K. Soczynska is a recipient of the Eli
Lilly Canada Fellowship Award.
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