DEPRESSION AND ANXIETY 30:515527 (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 cognitive 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 1865 were selected 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 aggregated 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 2030% 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 dysfunction (notably workforce performance) and MDD. No conventional antidepressant has been sufficiently studied and/or demonstrated robust procognitive
effects in MDD. Conclusions: Cognitive deficits in MDD are a principal mediator of psychosocial impairment, notably workforce performance. The hazards
posed by cognitive deficits in MDD underscore the need to identify a consensusbased neurocognitive battery for research and clinical purposes. Interventions
(pharmacological, behavioral, neuromodulatory) that engage multiple physiological systems implicated in cognitive deficits hold promise to reduce, reverse,
and prevent cognitive deficits. Depression and Anxiety 30:515527, 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,

Canada
2 Mood Disorders Psychopharmacology Unit, University Health
Network, Toronto, Canada
3 Department of Psychiatry, University of Toronto, Toronto,
Canada
4 Department of Pharmacology, University of Toronto, Toronto,
Canada
5 Centre for Neuroscience Studies, Queens University,
Kingston Canada


C 2013 Wiley Periodicals, Inc.

Contract grant sponsor: Takeda Pharmaceutical Company, Ltd.

Correspondence

to: Roger S. McIntyre, MD, FRCPC, Mood Disorders Psychopharmacology Unit, University Health Network, University of Toronto, 399 Bathurst Street, Toronto, ON, Canada M5T
2S8. E-mail: roger.mcintyre@uhn.ca
Received for publication 5 November 2012; Revised 4 January
2013; Accepted 4 January 2013
DOI 10.1002/da.22063
Published online 6 May 2013 in Wiley Online Library
(wileyonlinelibrary.com).

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McIntyre et al.

INTRODUCTION

ajor depressive disorder (MDD) is a multidimensional 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 recurrence, 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 performance) 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 identifying determinants of functional impairment. Available
evidence indicates that cognitive dysfunction is a critical mediator of adverse psychosocial outcomes in this
population.[57]
The Diagnostic and Statistical Manual of Mental Disorders Fourth Edition Text Revision (DSM-IV-TR)
identies cognitive impairment (i.e., poor concentration or indecisiveness) as a criterion item of a major
depressive episode (MDE). Cognitive complaints during the symptomatic and remitted phases are commonly
reported by individuals with MDD.[3, 4, 6, 8] When compared to other severe mental disorders (e.g., schizophrenia, 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 neurobiological substrate(s) of cognitive dysfunction in this
population, to determine the contribution of cognitive
dysfunction to psychosocial impairment, and to primarily evaluate the procognitive effects of treatment (regardless of modality).
Replicated evidence indicates that cognitive dysfunction causes and maintains psychosocial impairment in
severe mental disorders.[57] Moreover, decits in cognitive function in adults under the age of 65 with MDD
cannot be sufciently explained by age-related cognitive changes. Available evidence suggests that cognitive
dysfunction is a critical determinant of functional outcome 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 decits, enhancing
cognitive function and/or preventing their occurrence in
MDD remain unanswered. A general impression, albeit
based on relatively few empirical studies, is that cognitive decits are suboptimally treated with conventional
treatment approaches [e.g., selective serotonin reuptake
inhibitors (SSRIs)].[911]
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 redene how remission should be conceptualized.[6] Studies assessing
temporality of onset provide supporting evidence that
in some individuals, cognitive dysfunction may predate
the onset of the rst MDE.[12] Cognitive dysfunction
can be disaggregated into two broad interrelated categories: (1) decits in one or more cognitive domain(s)
or (2) cognitive bias: representing attentional allocation toward negatively valenced stimuli and/or aberrant
interpretation of social cues. It could be further surmised that cognitive bias represents a trait characteristic
in individuals who are temperamentally predisposed to
MDD (e.g., neuroticism). The preponderance of evidence indicates that cognitive decits are a consequence
and/or residual phenomenon of MDD and in relatively
fewer cases may be an antecedent to MDD. (The notion that cognitive decits 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 performance in nongeriatric, adult MDD samples. Selective
serotonin reuptake inhibitors (SSRIs), selective norepinephrine inhibitors (SNRIs), dopamine modulators
(bupropion), and norepinephrine inhibitors (reboxetine) have been reported to improve cognitive performance in adults with MDD.[1318] There is also
a paucity of evidence comparing the effects of different classes of antidepressants.[1618] Questions pertaining to the degree to which the improvement in
cognitive decits can be dissociated from the effect of other MDD psychopathology domains (e.g.,
chronicity, subtype of MDD, number and duration of
MDEs) and/or comorbidities have been insufciently
addressed.
The overarching aim of this review is to describe the
role of cognitive dysfunction as a determinant of functional outcome in MDD. Toward this aim, we succinctly
review (1) cognitive decits and their determinants in
adults with MDD 65 years old or younger (i.e., 1865
years) and (2) the effect of treatment on cognitive performance. The secondary objectives of this review are to
identify underlying substrate(s) that subserve cognitive
decits and to propose treatment approaches that primarily aim to mitigate, reverse, and prevent decits 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 decits, dementia, and functional outcome. Studies enrolling subjects between
the ages of 1865 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 identied articles were also reviewed in order to identify any other original
reports that were aligned with the objectives of this paper.

Obj.

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Review: Cognitive Deficits and Functional Outcomes in MDD

RESULTS

TABLE 1. Common neurocognitive tests

NEUROCOGNITIVE TESTS

Cognitive domain

Table 1 contains a list of conventional instruments and batteries frequently administered for assessing cognitive function. The available tests measure
intellectual functioning, working memory, verbal learning and memory, attention and information processing
speed, executive function, psychomotor performance,
and global cognitive function. None of the foregoing
cognitive measures have been specically developed to
evaluate cognitive performance and/or its functional implications in the workforce.

Executive function
(concept
formation,
abstraction, set
shifting, set
maintenance,
planning,
self-monitoring,
divided attention)

COGNITIVE DEFICITS IN MDD

The interpretation of study outcomes as they pertain

to cognitive decits in MDD begins with a review of
methodological factors that may affect the interpretation of the data. First, available studies are often inclusive of heterogeneous sample compositions that have included mixed ages, disparate denitions of MDD, and
illness characteristics (e.g., age at onset, duration, number of episodes, depression subtype, presence or absence
of psychotic features) as well as treatments. Additionally,
the co-occurrence of medical and/or psychiatric conditions has not always been controlled. The relevance of
this latter observation is underscored by evidence indicating that comorbid conditions in MDD may exert
direct effects on cognitive performance (e.g., attention
decit/hyperactivity disorder, obesity).[19, 20] For examples of determinants of cognitive decits in MDD, see
Table 2.
Most studies evaluating cognitive dysfunction in
MDD have enrolled symptomatic and treated individuals whereas relatively fewer studies enrolled asymptomatic and/or individuals not receiving medication.
Most studies have evaluated cognitive function following the onset of MDD. However, there is little documentation reporting on cognitive performance prior to
the onset of an index MDE. A separate understudied issue relates to the impact of early childhood adversity on
cognitive measures in adult samples with MDD and its
moderational effect.[21]
A notable factor affecting interpretation of study results is the heterogeneity of neurocognitive tests and batteries. Most available studies include tests that evaluate
performance across several principal cognitive domains
(see Table 1). There is, however, no accepted gold
standard psychometric of cognitive function in MDD
that has been embraced by the research/clinical community. In contradistinction, there have been efforts to
agree upon a common set of tests for individuals with
primary psychotic disorders for both descriptive and
interventional research [e.g., measurement and treatment in research to improve cognition in schizophrenia
(MATRICS)]. In the clinical setting, subjective
complaints of cognitive decits are common.[2224]
Notwithstanding the ubiquity of cognitive complaints,

Attention and
processing speed

Working memory

Verbal learning and

memory

Visual learning and

memory

Neurocognitive tests
Wisconsin Card Sorting Test (WCST)
Trail-Making Test Part B (TMT B)
Stroop Colour-Word Interference Test
(SCWT)
Categories Test
Block Design (WAIS-R)
Picture Completion (WAIS-R)
Concept Shifting Task (CST)
Tower of London (TOL; CANTAB)
Stockings of Cambridge (SOC; CANTAB)
Intra/Extradimensional Shift Test
(CANTAB; IED)
Spatial Span (SSP; CANTAB)
Ruff Figural Fluency Test (RFFT)
Verbal FluencyLetter Fluency & Category
Fluency
Controlled Oral Word Association Test
(COWAT)
The Delis-Kaplan Executive Function
System (D-KEFS)
Digit Symbol Substitution Test (DSST;
WAIS-R)
Digit Span Forwards and Backwards
(WAIS-R)
Continuous Performance Task (CPT)
Reaction Time (RTI; CANTAB)
Choice Reaction Time (CRT; CANTAB)
Simple Reaction Time (SRT; CANTAB)
Trail-Making Test Part A (TMT A)
Paced Auditory Serial Addition Test
(PASAT)
Serial Sevens Subtraction Test (SSST)
Arithmetic (WAIS-R)
Digit Span Forwards and Backwards
(WAIS-R)
Delayed Recognition Span Test (DRST)
Spatial Working Memory (SWM;
CANTAB)
Letter-Number Sequencing (LNS; WMS-R)
Logical Memory (WMS-R)
n-Back Test
California Verbal Learning Test (CVLT)
Rey Auditory Verbal Learning Test
(RAVLT)
Rivermead Behavioral Memory Test
(RBMT)
Hopkins Verbal Learning Test Revised
(HVLT-R)
Logical Memory (WMS-R)
Verbal Paired Associates (VPA; WMS-R)
Visual Verbal Learning Test (VVLT)
Digit Span Forwards and Backwards
(WAIS-R)
Luria Verbal Learning Test (LVLT)
Serial Sevens Subtraction Test (SSST)
Verbal Recognition Memory Test (VRM;
CANTAB)
Visual Reproduction (WMS-R)
Benton Visual Retention Test (VRT)
Benton Visual Form Discrimination (VFD)

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McIntyre et al.

TABLE 2. Determinants of cognitive deficits in major

depressive disorder (MDD)

TABLE 1. Continued
Cognitive domain

Neurocognitive tests

Rey-Osterrieth Complex Figure Test

(ROCF)
Kimuras Recurring Figures Test (RFT)
Visual Verbal Learning Test (VVLT)
Pattern Recognition Memory (PRM;
CANTAB)
Spatial Recognition Memory (SRM;
CANTAB)
Delayed Matching to Sample (DMS;
CANTAB)
Paired Associates Learning (PAL;
CANTAB)
Matching Familiar Figures Test 2
(MFFT-20)
Language and verbal Controlled Oral Word Association Test
comprehension
(COWAT)
Verbal FluencyCategory Fluency & Letter
Fluency
Similarities (WAIS-R)
Vocabulary (WAIS-R)
Information (WAIS-R)
Comprehension (WAIS-R)
Token Test
Judgement of Line Orientation (JOLO)
Visuospatial/
Benton Visual Form Discrimination (VFD)
perceptual
Block Design (WAIS-R)
processing
Visuospatial Span Forwards and Backwards
(WMS-R)
Brief mental status
Mini Mental State Exam (MMSE)
General intelligence Ravens Progressive Matrices
Wechsler Adult Intelligence ScaleRevised
(WAIS-R)
National Adult Reading Test (NART)
Wechsler Test of Adult Reading (WTAR)
Test of Nonverbal Intelligence-3 (TONI-3)
Cognitive battery
Cambridge Neuropsychological Test
Automated Battery (CANTAB)
Wechsler Memory ScaleRevised
(WMS-R)
Wechsler Adult Intelligence ScaleRevised
(WAIS-R)
Victoria Symptom Validity Test (VSVT)
California Computerised Assessment
Package (CalCAP)
CNS Vital Signs
Massachusetts General Hospital Cognitive
and Physical Functioning Questionnaire
(CPFQ)
The Delis-Kaplan Executive Function
System (D-KEFS)
Psychomotor
Finger Tapping
performance
Grooved Pegboard Test
Purdue Pegs
The Go/No-go Association Task (GNAT;
Decision making
CANTAB)
and response
Information Sampling Task (IST;
control
CANTAB)
Cambridge Gambling Task (CGT;
CANTAB)
Induction
Big/Little Circle (BLC; CANTAB)

Depression and Anxiety

Age[86]
Age at onset[87]
Educational attainment[88]
Baseline depression severity[89]
MDD subtype[90]
Symptomatic status (i.e., remission vs. nonremission)[14, 30, 91]
Psychiatric comorbidity[92]
Medical comorbidity[93, 94]
Illness duration[9]
Episode frequency[32]
Treatment[66]
Childhood adversity[95, 96]

the congruence between subjectively reported and objectively measured cognitive decits is not consistent in
MDD.[25]
A common convention among extant studies is the
reporting and comparing of group means rather than
an emphasis on individuals who fall below a prespecied cut score for cognitive dysfunction [i.e., 1
2 standard deviations (SD) below the norm].[26] This
convention may inadvertently decrease the assay sensitivity and not provide a sufcient estimate of the magnitude of decits, and/or the functional implications, in
MDD. Moreover, the use of mean scores in parametric
statistics assumes normal distribution of the dependent
variable. As the mean scores inuence extreme values,
the emphasis on mean scores rather than the SD from
the normative population mean could underestimate the
magnitude of decits that affect a subgroup of individuals with MDD.[26] For example, individuals with MDD
fall, on average, 0.51 SD below the normal population
mean.[14]
Notwithstanding it is reported that approximately 25
50% of patients with MDD exhibit decits that are
more than 1 SD below the mean on at least one cognitive domain and as many as 48% score more than 2
SD below the mean.[26] A summary statement regarding
cognitive decits in MDD is that cognitive decits are
consistent, replicable, nonspecic, clinically signicant,
and of small to medium in effect size. The most replicated cognitive decits are in the domains of executive
function, working memory, attention, as well as general
and psychomotor processing speed (e.g., sensorimotor,
cognitive).[27] A limitation of the approach that denes
decits based on deviations from the standard population means is that it is not inclusive of individuals who
remain above the mean, possibly due to cognitive reserve (e.g., education, occupation, intelligence),[28] but
report deterioration compared with baseline. It could be
hypothesized that these uncaptured decits likewise
contribute signicantly to relative functional decline in
these individuals.
The conventional assumption has been that cognitive
decits in MDD are a consequence or a residual feature of an acute MDE. For example, individuals with

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Review: Cognitive Deficits and Functional Outcomes in MDD

remitted MDD often exhibit persisting cognitive decits

in measures of attention, executive function, and verbal
memory.[29, 30] There have been relatively few studies
evaluating the temporality of onset, wherein cognitive
decits are documented prior to the onset of MDD.
Notwithstanding the paucity of data, a longitudinal,
population-based study has reported a signicant association between episodic memory function and emergent
depressive symptoms during a 2-year follow-up.[31]
A separate study that broadly aimed to identify premorbid markers of depression in a population-based
sample of nondepressed individuals (N = 708) evaluated prospectively over a 3-year period reported that
female gender, lower educational attainment, low social support, nancial strain, and poor episodic memory
(but not verbal uency, psychomotor speed, or mental speed) were associated with an increased risk of
depression.[12] These results suggest that hippocampaldependent memory may be abnormal prior to the clinical
presentation of depression.[12] The persistence of cognitive decits in asymptomatic individuals as well as the
identication of cognitive decits prior to the presence
of symptomatic depression indicates that in many individuals, cognitive decits can be conceptualized as a
core decit 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 signicantly associated with
the presence of cognitive decits.[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 ScaleRevised), a surrogate marker of hippocampal function, decreases approximately 23% with
each MDE, up to four episodes.[32] This decrement
in memory parallels results from morphometric studies that have documented volumetric reduction in the
hippocampus in MDD with a more pronounced decrease observed during the rst several episodes.[32, 34]
Current illness severity was the major determinant of
performance, as opposed to the intensity of their previous depressive history (i.e., the number and length
of past episodes). However, following clinical response
at the second visit, the length of previous depressive history became more signicant than current
symptoms.[32, 34]
Not all reports identify episode frequency as a determinant of cognitive decit. For example, a metaanalysis of cognitive decits in rst episode MDD
reported small-to-moderate effect size decreases in psychomotor speed, attention, visual and learning memory
as well as all aspects of executive function.[27] The presence of cognitive decits during the rst MDE as part
of MDD indicates that cognitive performance represents a target for early identication, measurement, and
intervention.[27, 35]
Taken together, there are multiple determinants of
cognitive outcome in MDD: heterogeneity of sample

composition, treatment regimens, patterns of comorbidity, denitions of depression and cognition measures, as
well as insufcient adjustment for early childhood adversity and colinearity, are major methodological limitations. Notwithstanding cognitive decits 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 signicant component of the overall
disability and cost associated with depression relates to
impaired workplace performance.[4]
The effect of neurocognitive decits as a mediator
of disability in individuals with MDD has been insufciently studied. Jaeger et al. reported that measures of attention, ideational uency, nonverbal (i.e., visuo-spatial)
and learning domains were highly associated with disability 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 subjective and/or objective measures of cognitive performance 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 moderately 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 neuropsychological measure.[25] These results replicate and extend
observations of an association between cognitive decits
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 analysis of the European Study of the Epidemiology of
Mental Disorders (ESEMeD), a cross-sectional survey 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, Cognition/Concentration/Attention/Memory, Social Interaction, Discrimination, Embarrassment) articulated in the
WHO International Classication of Functioning, Disability, and Health were evaluated.[7] Cognition and embarrassment were the only determinants signicantly
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]
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McIntyre et al.

Taken together, cognitive decits in MDD are not

only characterized by poor performance on objective and
subjective measures, but also appear to be a principal mediator of functional impairment.[39, 40] This observation
underscores the prioritization of cognitive decits 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 rene the hypothesis that disparate domains of
psychopathology in MDD are subserved by abnormalities in the structure, function, and chemical
composition of fronto-subcortical circuitry.[42, 43] A preliminary study also suggests that brain activation patterns 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 maintain workplace performance.[44] Moreover, several nodal
structures (e.g., hippocampus, amygdala, anterior cingulate cortex) are susceptible to volumetric/functional
changes as a consequence of illness duration, episode
frequency, and severity.[34, 43, 45] The neurochemical abnormalities that are well documented in individuals with
MDD can be conceptualized as a consequence of aberrant cellular functioning within the implicated neural
circuits.[4648] For example, disturbances in monoamine
systems, notably catecholamine systems, have been documented to play a role in attentional and executive
function decits.[49]
A derivative of this hypothesis is that the neurobiological correlates (i.e., neural circuits) of cognitive function
and decits, overlap with those implicated in other components 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 cortical and subcortical structures.[43, 51] These alterations
may mediate decits 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 regulatorycounterregulatory hormone balance
(i.e., glucocorticoid-signaling abnormalities, insulin
resistance), immunoinammatory activation, neurotrophins [e.g., Brain-Derived Neurotrophic Factor
(BDNF)], and oxidative stress.[46, 5254] A separate, and
possibly related, observation is that recurrent MDD
is associated with an increased hazard for Alzheimers
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 neuropathologically conrmed Alzheimers brain.[55] Moreover,
cognitively intact adults with MDD manifest lower
cerebrospinal uid 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] Accumulating evidence supports the hypothesis that alterations in insulin signaling may be relevant to neurocognitive decline in subpopulations of individuals with
MDD. For example, insulin resistance and diabetes mellitus type 2 are associated with cognitive decits 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 intracellular signaling cascades thereby resulting in neuronal/glial
loss and neurocognitive decline.[59, 60]
The default mode network (DMN), a proposed network of neural circuits that connects cortical and subcortical structures, may be relevant to cognitive function.[61]
The DMN comprises several nodal structures including
the ventralmedialprefrontal cortex, posterior cingulate/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 decits are a dening 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, modanil, an agent with established procognitive effects by enhancing catecholamine neurotransmission, augments deactivation in the major nodal structures of the DMN.[61]
In summary, the pathoetiological model in MDD
posits structural and functional disturbances in interconnected neural circuits and distributed networks. The
substrates that subserve cognitive performance in MDD
have overlapping and discrete components from the
substrates subserving affective processing; rening the
model subserving domains of psychopathology in MDD
hold promise to inform interventional strategies for cognitive decits in MDD.
THE EFFECT OF INTERVENTION ON
COGNITIVE DEFICITS IN MDD

All commercially available and approved conventional

antidepressants augment central indolamine and/or catecholamine neurotransmission.[64, 65] This pharmacodynamic prole provides the basis for hypothesizing that
antidepressants, in addition to mitigating both the mood
and vegetative symptoms of an MDE, would also be expected to ameliorate cognitive decits. There are, however, relatively few studies that have primarily aimed
to evaluate the effect of conventional antidepressants

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Review: Cognitive Deficits and Functional Outcomes in MDD

on cognitive performance in nongeriatric, adult MDD

samples.[1315] Available evidence indicates that SSRIs,
SNRIs, dopamine modulators (bupropion), and norepinephrine inhibitors (reboxetine) improve cognitive
performance in adults with MDD.[1618] There are also
relatively few studies that have compared the cognitive
effects of different classes of antidepressants on cognitive function.[1618] Insufciently answered questions include the degree to which the improvement in cognitive
decits can be dissociated from the effect on other MDD
psychopathology domains.
Herrera-Guzman et al. reported on the cognitive effects 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 motor performance.[16, 66] Duloxetine was superior to escitalopram on episodic and working memory whereas
no signicant differences between the antidepressants
were observed on measures of attention and executive
function.[16, 66]
Raskin et al. sought to determine the effect of duloxetine versus placebo on several measures of cognitive
performance.[10] A study in older adults (6290 years of
age) is reviewed as, to our knowledge, it is the only study
that primarily aimed to evaluate a conventional antidepressants ability to mitigate cognitive decits in a cohort
of adults with MDD.[10] They reported that when compared to placebo, 8 weeks of treatment with duloxetine
signicantly 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 Substitution Test (DSST)], visual attention and executive
function (i.e., Two-Digit Cancellation Test), and working memory/executive function (i.e., Letter-Number Sequencing 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 receptor antagonism, 5-HT1B receptor partial agonism,
5-HT1A receptor agonism, and inhibition of the 5-HT
transporter. In addition to its effect on indolamine signaling, vortioxetine also increased central neurotransmission of noradrenaline, dopamine, acetylcholine, and
histamine.[67] Vortioxetine has demonstrated antidepressant efcacy in MDD in adult and elderly populations as well as in adults with generalized anxiety
disorder.[68, 69] In addition to antidepressant properties, vortioxetine has demonstrated cognitive-enhancing
properties in animal and human studies.[70] For example, vortioxetine showed statistically signicant improvement on acquisition and delayed recall (as measured by the Rey Auditory Verbal Learning Test), as
well as information processing speed (as measured by

the DSST) in a group of elderly (N = 453) nondemented individuals with MDD.[68] In this study, duloxetine, the active control, also demonstrated improvement
on RAVLT, but not DSST.[68] A path analysis concluded
that 83% of the improvement on DSST with vortioxetine 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 benecial effects of vortioxetine in this study on cognitive performance were a
secondary outcome, providing an empirical basis for
evaluating the effect of this agent on cognition and consequently 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 interventions that engage multiple neurochemical systems
simultaneously may be more likely to improve cognitive performance when compared to interventions that
principally target a single system (e.g., SSRIs). In keeping with this view, it is not uncommon for practitioners to coprescribe mechanistically diverse agents (e.g.,
modanil, psychostimulants) and/or suggest behavioral
interventions (e.g., aerobic exercise) in addition to conventional antidepressant treatment with an aim to primarily target the cognitive domain. Hitherto, no Food
and Drug Administration (FDA) approved agent for depression has been purposefully evaluated to mitigate cognitive decits and improve psychosocial functioning in
MDD.

DISCUSSION
Several observations emanate from the synthesis of the
data reviewed herein.[3, 36, 71, 72] The functional impairments (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 workforce away from primary industry toward a skilled human capital economy will only amplify the importance of
diseases/disorders of the central nervous system (CNS)
and their actuarial costs.[3, 72, 74]
Cognitive dects in MDD are prevalent and may
represent a core dimension of psychopathology in
MDD.[31, 32, 75] Cognitive decits are often a persisting abnormality in individuals with MDD and in some
cases may predate the onset of clinically signicant
depressive symptoms.[12, 27] The observation that cognitive decits mediate psychosocial impairment (i.e.,
accounting for a signicant percentage of variance) and
intervention.[7, 26, 74] When compared with severe mental disorders (e.g., schizophrenia, bipolar disorder), relatively less emphasis has been given to the hazards posed
by cognitive decits in MDD. Along with the methodological limitations that affect inferences and interpretations that may be drawn from the extant data pertaining to cognitive decits in MDD, there is no gold
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McIntyre et al.

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

Author

Year

Ferguson et al.

2003

Constant et al.

Treatment

Cognitive tests

74 MDD (age range =

1865)

Reboxetine (810 mg/day;

N = 25)
Paroxetine (2040
mg/day; N = 23)
Placebo (N = 26)

SRT, Digit Vigilance,

CRT, Numeric WM,
Word Recognition, and
Critical Flicker
Frequency

2005

20 MDD (mean age =

47.67)
26 healthy controls (mean
age = 48.85)

Sertraline (5075 mg/day)

Phasic Alertness Task,

Classic SCWT, and the
Supraliminal and
Subliminal Emotional
Stroop test

Gualtieri et al.

2006

38 drug-free MDD (mean

age = 38.11, SD = 9.95)
31 MDD antidepressant
monotherapy
responders (mean age =
43.55, SD = 10.68)
69 healthy controls (mean
age = 41.30, SD =
11.40)

Citalopram (N = 1)
Fluoxetine (N = 3)
Escitalopram (N = 8)
Paroxetine (N = 3)
Mirtazapine (N = 1)
Trazodone (N = 1)
Venlafaxine (N = 5)
Bupropion (N = 6)
Sertraline (N = 3)

CNS Vital Signs

Gualtieri et al.

2007

81 MDD (mean age =

43.85)
27 healthy controls (mean
age = 43.85)

Bupropion (N = 27)
Venlafaxine (N = 27)
SSRI (N = 27)

CNS Vital Signs

Raskin et al.

2007

311 MDD
Duloxetine (N = 207;
mean age = 72.6, SD =
5.7)
Placebo (N = 104; mean
age = 73.3, SD = 5.7)

Duloxetine (60 mg/day; N

= 207)
Placebo (N = 104)

Verbal Learning and

Recall Test, DSST,
Cancellation Test, LNS

Depression and Anxiety

Population

Cognitive
decits/improvements
Reboxetine signicantly
improved sustained
attention and speed of
cognitive functioning
compared with baseline
No signicant changes or
trends in this direction
were observed in
individuals receiving
either paroxetine or
placebo
MDDs had psychomotor
slowing associated with
attentional and
executive disturbance
Following rst weeks of
treatment, a benecial
effect on psychomotor
slowing on attentional
and executive functions
was observed
Untreated MDDs had
global
neuropsychological
impairment.
Successfully treated
MDD`s performance
improved, but not
normalized
Specic
depression-related
decits were observed
in executive function
and processing speed,
but not in memory,
psychomotor speed, or
reaction time
SSRI group scored
signicantly below
controls in tests of
psychomotor speed,
cognitive exibility, 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
Duloxetine demonstrated
signicantly greater
improvement versus
placebo. MDD with
duloxetine treatment
improved verbal
learning and memory

Review: Cognitive Deficits and Functional Outcomes in MDD

523

TABLE 3. Continued
Author

Year

Population

Treatment

Herrera-Guzman
et al.

2010

73 MDD
SSRI (N = 36; mean age
= 32.91, SD = 8.73)
SNRI (N = 37; mean age
= 33.21, SD = 8.61)
37 healthy controls (mean
age = 33.05, SD = 8.04)

Escitalopram (10 mg/day;

N = 36)
Duloxetine (60 mg/day; N
= 37)

Vocabulary, Digit Span

and SWM, Rapid
Visual Information
Processing, DMS,
SCWT, IED, SOC

Herrera-Guzman
et al.

2010

73 MDD
SSRI (N = 36; mean age
= 32.91, SD = 8.73)
SNRI (N = 37; mean age
= 33.21, SD = 8.61)
37 healthy controls (mean
age = 33.05, SD = 8.04)

Escitalopram (10 mg/day;

N = 36)
Duloxetine (60 mg/day; N
= 37)

Vocabulary, Digit Span,

AVLT, PRM, PAL,
DMS, SRM, RTI,
SCWT

Herrera-Guzman
et al.

2010

73 MDD
SSRI (N = 36; mean age
= 32.91, SD = 8.73)
SNRI (N = 37; mean age
= 33.21, SD = 8.61)
37 healthy controls (mean
age = 33.05, SD = 8.04)

Escitalopram (10 mg/day;

N = 36)
Duloxetine (60 mg/day; N
= 37)

Vocabulary, SWM,
RAVLT, PAL, SOC,
Rapid Visual
Information Processing

Hinkelmann et
al.

2012

N = 52 MDD with SSRI

treatment and add-on
treatment modulating
the mineralocorticoid
receptor
N = 50 healthy subjects

Baseline
Escitalopram (1020
mg/day; N = 52)
Add-on treatment
MR-agonist
udrocortisone (0.2
mg/day; N = 19)
MR-antagonist
spironolactone (100
mg/day; N = 22)
Placebo (N = 11)

RAVLT, Digit Span F and

B, ROCF, Cancellation
test, TMT A and B

standard to measure cognitive decits in research

settings and/or to succinctly and comprehensively measure cognitive decits in the clinical ecosystem. Moreover, as interest in patient-reported outcomes in psychiatric and medical disorders increases, there will be
a need to identify not only objective, but also subjective measures of cognitive functions that are valid,

Cognitive tests

Cognitive
decits/improvements
SSRI and SNRI
treatments both
improved WM,
attention, and all
executive functions.
However, MDD`s
cognitive function did
not improve enough to
reach levels of control
subjects
SSRI and SNRI
treatments both
improved episodic
memory and, to a lesser
extent, WM, mental
processing speed and
motor performance.
SNRI was superior to
SSRI at improving
episodic memory and
WM
MDDs in remission
showed decits in verbal
and visual episodic
memory, sustained
attention, mnemonic
and strategic aspects of
WM, and planning.
MDDs in recovery
showed the same
neuropsychological
decit pattern. MDDs
treated with SSRI
showed more
impairment in episodic
visual and verbal
memory than those
treated with SNRI
MDD performed worse
compared with healthy
controls (Digit Span
Forward, ROCF,
Cancellation Test),
indicating ongoing
relative cognitive
decits in these
domains. No differences
between the three
treatment groups were
observed over time

reliable, and have utility for personalizing treatment

interventions.[76]
MDD is a heterogeneous phenotype in phenomenology and pathoetiology. There is no single disease model
that will sufciently explain the panoply of abnormalities observed across disparate populations. Admittedly
complex, a conceptual framework of disease modeling in
Depression and Anxiety

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McIntyre et al.

MDD that would be comprehensive and coherent would

posit that there are multiple (i.e., hundreds, if not thousands) disease pathways in MDD. Succinct neurobiological substrate(s) of neurocognitive dysfunction is not
currently available. Notwithstanding available evidence
implicates altered cellular, synaptic, and circuitry abnormalities in MDD manifesting as disturbances in central
neurotransmitter signaling.[46, 5254, 77]
Robust therapeutic interventions specically targeting cognitive decits in MDD are not currently
available, largely due to insufcient empirical observation. Notwithstanding available evidence indicates
that targeting multiple monoamine systems mitigates
cognitive decits independent of its effect on other
depressive symptoms.[10, 16, 66] The complex pathoetiology of cognitive decits provides the basis for hypothesizing that interventions capable of engaging
multiple physiological systems may be differentially effective for this domain of psychopathology. Moreover,
it remains a testable hypothesis that mitigating cognitive decits in MDD would result in an improvement in overall psychosocial performance, notably in the
workforce.
Rening disease models in MDD will provide a platform for identifying genuinely novel, pharmacological
treatment approaches to treat, reverse, and prevent cognitive decits in MDD (Table 3). Extrapolating from results reported in schizophrenia and bipolar disorder, it is
reasonable to expect that some adults with MDD would
be candidates for cognitive remediation and neurorehabilitative activities/endeavors.[7882] Moreover, novel
neuromodulatory approaches [e.g., repetitive Transcranial Magnetic Stimulation (rTMS)], complementary alternative medicine (e.g., N-acetyl-cysteine), and behavioral interventions (e.g., aerobic exercise) may also have
a place in the armamentarium against cognitive decits
in MDD beyond resolution of the acute episode.[13, 8385]
Acknowledgments. This review was sponsored by
the Takeda Pharmaceutical Company, Ltd., as part of
a joint clinical development program with H. Lundbeck 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 conicts of
interest. Joanna K. Soczynska is a recipient of the Eli
Lilly Canada Fellowship Award.

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