Open Journal of Depression
2013. Vol.2, No.4, 45-53
Published Online November 2013 in SciRes (http://www.scirp.org/journal/ojd) http://dx.doi.org/10.4236/ojd.2013.24010
Open Access 45
Cognitive and Psychosocial Improvements Following
Aripiprazole Augmentation of SSRI Antidepressant Therapy in
Treatment Refractory Depression: A Pilot Study
Tracy L. Greer*, Prabha Sunderajan, Bruce D. Grannemann, Madhukar H. Trivedi
Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, USA
Received June 28th, 2013; revised August 1st, 2013; accepted August 10th, 2013
Copyright © 2013 Tracy L. Greer et al. This is an open access article distributed under the Creative Commons
Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the
original work is properly cited.
Functional impairments are a common concern for individuals with major depressive disorder (MDD) that
does not resolve with initial antidepressant treatment. Such concerns include cognitive difficulties, such as
impaired executive functions, which can be particularly disruptive to daily function. There is a need to
evaluate potential augmentation strategies for depressed individuals who do not adequately respond to
initial antidepressant treatment. Aripiprazole is an FDA-approved adjunctive treatment to antidepressants
for MDD, and because of its effect on both dopaminergic and serotonergic systems, may be of particular
benefit to cognitive functioning. This study evaluated depressive symptom severity, cognitive function,
and psychosocial function before and after six weeks of open-label aripiprazole augmentation treatment in
patients with MDD who did not fully respond to selective serotonin reuptake inhibitor treatment. Partici-
pants endorsed difficulty with concentration and decision-making at study entry. Significant decreases
were observed for depressive symptoms, and significant increases were found in executive function
measures and measures of psychosocial function and quality of life. These preliminary data suggest that
aripiprazole augmentation may yield functional benefits when used as an adjunctive treatment in MDD,
and support the need for further investigation of aripiprazole and other augmentation strategies to specifi-
cally evaluate functional outcomes in MDD.
Keywords: Neurocognition; Psychosocial Function; Major Depressive Disorder; Treatment Resistance
Background
Major depressive disorder (MDD) is a debilitating, chronic
disorder that is of worldwide concern (Cuijpers et al., 2012),
particularly since it is estimated to become the most burden-
some disease in high-income countries, and second-most over-
all, by the year 2030 (Mathers & Loncar, 2006). The consensus
of treatment guidelines for major depressive disorder is that the
goal of treatment should be symptomatic remission, which is
characterized by minimal absence of depressive symptoms
(Davidson, 2010). However, it is often the case that despite
achieving remission, residual symptoms remain that are still
bothersome to those with MDD, and if left untreated may con-
tribute to further decline and relapse. In fact, greater than 90%
of remitters have at least one residual symptom (Nierenberg et
al., 2010), and cognitive impairments are a common residual
symptom. Even with adequate symptomatic treatment response
(McClintock et al., 2011) and remission (Nierenberg et al.,
2010; Zimmerman et al., 2012) of overall depressive symptoms,
cognitive impairments remain a concerning residual symptom
warranting treatment.
Cognitive impairments in depression are most frequently
noted on tasks assessing executive function, declarative mem-
ory, and attention (Veiel, 1997; Landro et al., 2001). Impaired
cognitive function in depression has been strongly associated
with disability in depression and many other psychiatric disor-
ders (Jaeger et al., 2006). Disruptions in cognitive function can
have wide reaching implications on quality of life, affecting
many areas of life such as relationships, work, school, and ma-
nagement of basic needs (e.g., taking care of finances and other
life responsibilities). Because of the negative consequences of
functional impairments, an alternative goal to symptomatic
remission is achieving wellness (Keller, 2003; McIntyre et al.,
2006), which incorporates restoration of function in addition to
symptomatic and pathophysiologic change. To achieve such a
goal, it is imperative that the field begins to include functional
measures and targeted treatments for specific symptoms to
improve the quality of life and functioning of depressed indi-
viduals (Greer et al., 2010). Some potential treatments for cog-
nitive impairments such as psychostimulants and cholinesterase
inhibitors have yielded benefits in some cases, but they often
are associated with unwanted side effects, and they require
significant monitoring (Greer et al., 2010; Kurian et al., 2009).
Thus, it is critical to continue identifying treatments that will
improve cognition and other functional outcomes in depressed
individuals.
Aripiprazole is an FDA-approved adjunctive treatment to an-
tidepressants for MDD. When added to ongoing antidepressant
treatment that is not fully resolving depressive symptoms,
*Corres
p
ondin
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author.

T. L. GREER ET AL.
Open Access 46
aripiprazole increases the likelihood of remission (Berman et al.,
2009; Nelson et al., 2012). It is well-tolerated, even after long-
term (e.g., a year) administration, with primary side effects
being weight gain, akathisia, and fatigue (Berman et al., 2011).
However, the ability for aripipriazole to address specific func-
tional outcomes has been sparsely investigated. Thase et al.
(2008) examined mean changes in the Sheehan Disability Scale
(SDS) scores between depressed individuals augmented with
aripiprazole vs. placebo and found that aripiprazole augmenta-
tion was associated with significantly greater reductions in
mean SDS scores, as well as with the individual items measur-
ing symptom interference with social and family life. The effect
of aripiprazole augmentation on health-related quality of life
and health utility has been compared to augmentation with
other atypical antipsychotics based on data from the National
Health and Wellness Survey, and aripiprazole augmentation
showed significantly greater benefits in measures of mental
health, general health, emotional role limitations, bodily pain,
and health utility (Kalsekar et al., 2012). To our knowledge, no
study has examined cognitive changes as an outcome following
aripiprazole augmentation. Reimherr et al. (2010) conducted a
pooled analysis examining symptom-level improvements in
core symptoms of depression as measured by the Montgom-
ery-Asberg Depression Rating Scale (MADRS) and the Inven-
tory for Depressive Symptomatology, Self-Report (IDS-SR).
They did not find that aripiprazole augmentation was superior
to placebo augmentation on concentration symptoms as meas-
ured by the items addressing that symptom on either scale;
however, it is not clear how many participants endorsed con-
centration difficulties at baseline.
Aripiprazole has a distinct pharmacological profile that has
been speculated to explain its efficacy as an augmentation agent
(Nelson et al., 2008), and supports the possibility of improved
cognitive function as well. Aripiprazole is unique from other
antipsychotics in that it stabilizes both dopaminergic and sero-
tonergic systems. It affects serotonergic activity via mecha-
nisms that are identical to agents that have been established as
effective antidepressants. Specifically, aripiprazole is a partial
agonist at 5-HT1A receptors and an antagonist at 5-HT2 recep-
tors (Burris et al., 2002). In comparison to other commonly
used atypical or typical antipsychotic agents, aripiprazole has a
higher affinity for 5-HT1A receptors, and has an affinity for
5-HT2 receptors that is higher than or comparable to most other
antipsychotics agents (surpassed only by risperidone and zipra-
sidone) (Burris et al., 2002; Bymaster et al., 1996; Seeger et al.,
1995). Aripiprazole is also a partial agonist of both D2 and D3
dopaminergic receptors (Tadori et al., 2008). D2 and D3 ago-
nism has been associated with pro-cognitive effects, and has
shown some promise in improving cognition as an adjunctive
treatment in bipolar disorder (Burdick et al., 2012).
This study examined open-label aripiprazole augmentation of
selective serotonin reuptake inhibitor (SSRI) treatment in de-
pressed individuals who endorsed difficulties with concentra-
tion and decision-making that were significant enough to dis-
rupt their functioning. This study was conducted to gather pre-
liminary data for assessment of the following: 1) the effect of
aripiprazole augmentation on depressive symptom severity,
psychosocial function and cognitive function, and 2) the rela-
tionship between psychosocial function and cognitive function
in MDD. We hypothesized that aripiprazole augmentation
would be associated with reductions in symptom severity, and
with improved performance on measures of psychosocial and
cognitive function, particularly measures of executive function.
Study Design
Participants
The study protocol and informed consent form were ap-
proved by the University of Texas Southwestern Medical Cen-
ter at Dallas Institutional Review Board. Eligible participants
with major depressive disorder were treated in the community
with one of three SSRIs (escitalopram, citalopram, or sertraline)
for 8 - 12 weeks and experienced residual depressive symptoms
that prompted them to seek additional treatment and respond to
study advertisements. The Structured Clinical Interview for
DSM-IV Axis I Disorders, Clinician-Rated version (SCID-CV)
was used to diagnose MDD and rule out excluded comorbid
psychiatric disorders. Residual symptoms were quantified as a
Hamilton Rating Scale for Depression, 17-item, (HRSD17)
score of 14 or greater or a Clinical Global Impression Scale-
Severity (CGI-S) score of 3 or greater. Participants had to re-
port difficulties with concentration or cognition and score 2 or
greater on the 30-item Inventory for Depressive Symptomatol-
ogy-Clinician-Rated (IDS-C30) item measuring this symptom
(#15: Concentration and Decision Making). Organic cognitive
deficits that could confound study outcomes were ruled out
using the Mini-Mental State Examination (MMSE). Additional
exclusions included the presence of an untreated or unstable
comorbid medical condition, known cardiovascular disease or
seizure disorder, certain comorbid psychiatric disorders (current
or past psychotic disorder, bipolar disorder, schizophrenia or
schizoaffective disorder, anorexia, bulimia, obsessive compul-
sive disorder, alcohol or substance abuse or dependence within
the last 6 months, or high suicide risk), or concomitant phar-
macological or psychotherapeutic treatment. A urine pregnancy
test was performed as clinically indicated for women who were
able to have children and wished to participate in this research.
Eligible participants completed a comprehensive baseline as-
sessment battery that included measures of depressive symp-
toms, psychosocial function, and cognitive function, as de-
scribed below.
Assessment of Depressive Symptoms
The HRSD17 and IDS Self-Report (IDS-SR30) were used to
assess severity of depressive symptoms at screening, baseline,
and weekly thereafter. The HRSD17 (Hamilton, 1960) is a clini-
cian-administered rating scale designed to assess the severity of
symptoms in patients diagnosed with depression and is the most
widely used symptom severity measure for depression. The
IDS-SR30 (Rush et al., 1986) is a 30-item, depression-specific
symptom severity rating scale designed to measure the specific
signs and symptoms of depression, including melancholic and
atypical features. Scores range from 0 to 84 with higher scores
representing greater severity of depressive symptoms.
Assessment of Psychosocial Function
The Short-Form Health Survey (SF-36) (Ware & Snow, 1993)
was used to assess quality of life and general health. This
measure is comprised of two major subscales: Mental and Phy-
sical. The Quality of Life Enjoyment and Satisfaction Ques-
tionnaire, General Activities (Q-LES-Q) (Endicott & Nee, 1993)
was used to measure satisfaction and enjoyment in various

T. L. GREER ET AL.
Open Access 47
domains of function: physical health, feelings, work, household
duties, school/course work, leisure time activities, and social
relations. The Work and Social Adjustment Scale (WSAS)
(Mundt et al., 2002) was used to identify functional impairment
attributed to depression. The WSAS is a 5-item self-report, and
each question is rated on a 0 to 8 scale, with 0 indicating no
impairment, and 8 indicating very severe impairment. The
WSAS has acceptable internal consistency (Cronbach’s alpha
= .70 to .94) and test re-test reliability (r = .73). WSAS scores
above 20 suggest moderately severe or worse psychopathology.
These measures were collected at baseline, Week 3, and Week
6.
Assessment of Cognitive Function
The National Adult Reading Test-Revised (NART-R) (Blair
& Spreen, 1989) was given at baseline to assess premorbid
intelligence. Clinician-rated and self-reported cognitive func-
tion was assessed via the Inventory for Depressive Symptoma-
tology item “Concentration and Decision Making”. The Cam-
bridge Neuropsychological Test Automated Battery (CANTAB)
(Cambridge Cognition Limited, 2004) was used to assess pre-
and post-treatment cognitive function. CANTAB is a compre-
hensive neuropsychological testing battery that has been used to
assess cognitive function in a wide variety of brain disorders,
including mood disorders. Tasks selected for use in this study
have previously shown performance differences between de-
pressed patients and healthy controls. The tasks selected repre-
sented each of the following domains: Attention, Visual Mem-
ory, Executive Function/Set-shifting and Working Memory,
Executive Function/Spatial Planning, Decision Making and
Response Control, and Verbal Learning and Memory. These
tasks measure domains (attention, perception, working memory,
declarative memory, effortful control) that are consistent with
those included in the National Institute of Mental Health Re-
search Domain Criteria (NIMH RDoC) initiative (Sanislow et
al., 2010), which aims to re-assess pathophysiology of chronic
mental illnesses through a dimensional approach (Insel et al.,
2010). An overall description of each task assessed in this study
is provided below.
1) Attention Domain Tasks: Motor Screening (MOT)—
screens for visual, movement and comprehension difficulties;
Big Circle/Little Circle (BLC)—a simple attention measure that
tests comprehension, learning and reversal of a rule; Reaction
Time (RTI)—measures speed of response to both predictable
and unpredictable visual stimuli;
2) Visual Memory Domain Tasks: Delayed Matching to
Sample (DMS)—an object recognition task using complex
visual patterns in which the choice is presented either simulta-
neously with the sample or after a brief delay; Paired Associ-
ates Learning (PAL)—a delayed response visual memory and
learning task; Pattern Recognition Memory (PRM)—assesses
visual spatial recognition memory;
3) Executive Function/Set-Shifting and Working Memory
Domain Tasks: Intradimensional/Extradimensional Shift (IED)
—examines set-shifting and flexibility of attention by testing
both simple and more complex rule acquisition and reversal;
Spatial Working Memory (SWM)—an executive function task
assessing retention and manipulation of items in working me-
mory, with the ability for assessment of perseverative (redun-
dant) errors;
4) Executive Function/Spatial Planning Domain Task:
Stockings of Cambridge (SOC)—an executive function task
based on the Tower of London test that assesses spatial plan-
ning;
5) Decision Making and Response Control Domain Task:
Affective Go/No-go (AGN)—assesses information processing
biases and inhibitory control for positive and negative stimuli;
6) Verbal Learning and Memory Domain Task: Verbal Rec-
ognition Memory (VRM)—a measure of immediate and de-
layed verbal recall and recognition.
Each task can generate multiple outcome measures (e.g., per-
cent correct, response latency), as described in Table 1. The
CANTAB battery was administered at baseline and following
six weeks of aripiprazole augmentation treatment by raters who
were blinded to symptom severity assessments.
Medication Management and Assessment of Safety
Participants were maintained on their entry-level dose of
SSRI and a flexible dose of 5 mg to 15 mg aripiprazole was
added to their SSRI for 6 weeks. Participants started at 5 mg
and went up to 15 mg only if clinically indicated and not con-
traindicated due to adverse effects. Participants met with a
study psychiatrist on a weekly basis during aripiprazole aug-
mentation for assessment of suicidality, side effects, adverse
events, and improvement. Vital signs were recorded at each
visit. The Frequency, Intensity, and Burden of Side Effects
Ratings (FIBSER) and Patient Rated Inventory of Side Effects
(PRISE) scales were used to assess side effects. The FIBSER
assesses the frequency, intensity, and degree of functional im-
pairment associated with side effects of treatment, and the
PRISE assesses specific types of side effects (e.g., sleep, sexual
function), which may or may not be associated with treatment.
Participants were assessed for possible abnormal involuntary
movements or extrapyramidal symptoms at every visit.
Statistical Analyses
The primary aim of the study was to determine the effect of
aripiprazole augmentation on depressive symptom severity,
psychosocial function and cognitive function. Changes in de-
pressive symptom severity and psychosocial function were
assessed via t-tests. Distributions of scores on the cognitive
measures were evaluated and due to the non-normal distribu-
tions of some measures, a non-parametric Signed Rank test was
used to evaluate changes in the cognitive measures. Because
this is a pilot study, results are reported if they were significant
at p < .05.
A secondary aim of the study was to assess the relationship
between changes in depressive symptoms, psychosocial func-
tion and cognitive function. Due to the size of the sample and
the non-normal distribution of some variables, we conducted a
series of Spearman rank correlations between the changes in
cognitive measures that were significant (post-pre treatment)
and changes from baseline to Week 3 and Week 3 to Week 6 on
the depressive symptom severity and psychosocial function meas-
ures.
Completion of the study was required for analyses since cog-
nitive data were obtained only at pre- and post-treatment time-
points.
Results
All participants provided written informed consent. Twenty-

T. L. GREER ET AL.
Open Access 48
Table 1.
Description of cognitive function outcome measures.
Task Acronym Outcome Measure Description
Training and Screening Attention Tasks
Big/Little Circle BLC Mean correct latency (ms) Speed of response showing how quickly subject touched the correct stimulus after it was
displayed on the screen
Mean percent correct (%) Percent of total correct responses
Reaction Time RTI Five-choice movement time (ms) Time taken to touch correct stimulus after release of the press pad
Five-choice reaction time (ms) Speed with which subject releases press pad in response to stimulus at one of five locations
Visual Memory
Delayed Matching to
Sample DMS Percent correct (all delays) (%)Percent of correct stimulus selection after stimulus was hidden at delays of 0 s, 4 s, and 12 s
Percent correct (simultaneous)
(%)
Percent of correct stimulus selection during simultaneous presentation of target stimulus
and distractors
Mean correct latency (all delays) Average speed of response where correct stimulus was selected in trials with simultaneous
presentation of target stimulus and distractors
Mean correct latency
(simultaneous)
Average speed of response where correct stimulus was selected in trials in which stimulus
was hidden at delays of 0 s, 4 s, and 12 s
Paired Associates
Learning PAL Mean trials to success Total number of trials required to correctly locate patterns/number of successfully completed stages
Total errors (adjusted) Total number of errors with adjustment for each stage not attempted due to previous failure
Total trials (adjusted) Total number of presentation required to correctly locate patterns in all stages
Pattern Recognition
Memory PRM Percent correct Percent correct responses
Mean correct latency (ms) Mean time to respond correctly
Executive Function
Intra/Extra
Dimensional
Set-Shifting
IED Stages completed Number of stages completed out of nine possible
Pre-ED errors Number of errors prior to the extra-dimensional shift
EDS errors Errors made in the extra-dimensional stage
Spatial Working
Memory SWM Strategy Calculated based on number of times participant begins a search with the same box for 6- and 8-box problems. Lower score indicates better use of strategy.
Between errors (4, 6, and 8
boxes)
Times the subject revisits a box in which a token was previously found; errors calculated for
4-, 6-, and 8-box trials
Executive Function/Spati al Planning
Stockings of
Cambridge SOC Problems solved in minimum moves
Number of times subject successfully completed a test problem in the minimum possible
number of moves
Mean initial thinking time (2, 3,
4, and 5 moves) Time taken to plan a problem solution for trials requiring 2, 3, 4, and 5 moves
Mean subsequent thinking time
(2, 3, 4, and 5 moves)
Speed of movement after the initial move has been made for trials requiring 2, 3, 4, and 5
moves.
Decision Making and Response Control
Affective Go/No-Go AGN Mean correct latency Mean time taken to respond correctly to each target word stimulus in all assessed blocks
Total omissions Total number of missed responses to targets in all assessed blocks
Total commissions Total number of responses to distractors in all assessed blocks
Verbal Learning and Memory
Verbal Recognition
Memory VRM Immediate free recall total correct Total number of words correctly recalled immediately following presentation of word list
Immediate free recall total novel
words
Total number of words recalled immediately following presentation of word list that were
not a part of the list
Immediate free recall total
perseverations
Total number of times a previously correctly recalled is repeated immediately following
presentation of word
Immediate recognition total
correct
Total number of words correctly recalled during presentation of word list that includes
correct targets and distractors
Immediate recognition total false
positives
Total number of distractors endorsed as correct responses during presentation of word list
that includes correct targets and distracters
Delayed recognition total correct Total number of words correctly recalled during presentation of word list that includes
correct targets and distractors following 20 min delay from original presentation of word list
Delayed recognition total false
positives
Total number of distractors endorsed as correct during presentation of word list that
includes correct targets and distractors following 20 min delay from original presentation of

T. L. GREER ET AL.
Open Access 49
six participants were screened for participation, and nine par-
ticipants were found to be ineligible for the following reasons:
presence of significant comorbid medical condition or abnor-
mal laboratory values (4), presence of other psychiatric disorder
or severity of symptoms (2), declined further participation (2),
and prohibited concomitant medication (1). Seventeen partici-
pants began augmentation treatment with aripiprazole. Thirteen
participants completed all six weeks of aripiprazole augmenta-
tion and thus were included in the analyses. Baseline demo-
graphic and clinical characteristics of the study participants are
provided in Table 2.
Depressive Symptom Severity
Significant mean reductions in depressive symptom severity
over the six weeks of aripiprazole augmentation were obtained
on both clinician-rated and self-report measures of depression
(see Figure 1). HRSD showed a mean difference of −11.38
(±4.3; t = 9.52, p < .0001) and IDS-SR a mean difference of
−17.54 (±11.64; t = 5.43, p = .0002) between baseline and
post-treatment. Of the thirteen completers, nine (53%) re-
sponded, defined by a 50% or greater reduction in HRSD score.
Seven (41%) remitted, as defined by achieving HRSD score of
7 or less.
Psychosocial F unction
Significant improvements in psychosocial function over the
six weeks of aripiprazole augmentation were obtained for the
Q-LES-Q and SF-36, and showed a trend toward significance
for the WSAS. On the Q-LES-Q, the pre-treatment mean of
2.73 ± .69 significantly increased to 3.49 ± .97 post-treatment, a
mean change of .81 ± .48 (t = 5.84, p = .0001). SF-36 scores
significantly increased from 39.62 ± 11.63 at pre-treatment
on the Mental subscale to 63.75 ± 28.05 post-treatment, a mean
change of 24.17 ± 25.30 (t = 3.31, p = .007), and from 68.50 ±
22.83 at pre-treatment on the Physical subscale to 82.92 ±
14.84 post-treatment, a mean change of 15.79 ± 22.75 (t = 2.40,
p = .035). On the WSAS, scores also improved, with a mean
score of 26.67 ± 8.51 at pre-treatment, decreasing to 17.67 ±
14.19, with a trend toward significance (mean difference =
Figure 1.
Clinician-rated (HRSD) and self-reported (IDS-SR) depressive
symptom severity significantly decreased with aripiprazole aug-
mentation. HRSD pre-treatment mean (SD) = 20.7 (5.0), post-
treatment mean = 9.3 (6.3); IDS-SR pre-treatment mean = 34.9
(9.9), post-treatment mean = 17.5 (11.6).
Table 2.
Baseline sample characteristics.
Baseline Variable MEAN OR % (± SD)
n = 17 MEAN OR % (± SD) n = 13
Age (years) 48.18 (± 7.95) 50.46 (± 7.34)
Male (%) 23.53
Female (%) 76.47
White (%) 82.35
Hispanic (%) 17.65
Education (years) 11.81* (± 4.75) 12.42+ (± 4.60)
Characteristics of Depression
Age of MDD Onset 28.62 (± 11.48)
Number of Previous Episodes 3.65 (± 4.86) 3.85 (± 5.58)
Length of Current Episode (months) 65.24 (± 60.72) 67.38 (± 67.44)
Baseline Symptom Severity
HRSD17 20.00 (± 4.50) 20.69 (± 4.97)
IDS-C30 34.65 (± 7.11) 34.85 (± 7.76)
IDS-SR30 34.38 (± 9.95)
Estimate d Intelligence
NART 104.85 (± 9.02)
*n = 16, +n = 12; MDD = Major Depressive Disorder; HRSD17 = Hamilton Rating Scale for Depression, 17-item; IDS-C30 = Inventory for Depressive Symptomatology—
Clinician-Rated, 30-item; IDS-SR30 = Inventory for Depressive Symptomatology—Self-Report, 30-item; NART = National Adult Reading Test.

T. L. GREER ET AL.
Open Access 50
7.82 ± 11.74, t = 2.21, p = .0516). Note that higher scores indi-
cate better function for the Q-LES-Q and SF-36 measures, where-
as lower scores indicate better function on the WSAS.
Cognitive Function
Significant changes in cognitive function were observed on
measures of executive function. Significant changes on differ-
ence scores were found on the Stockings of Cambridge Mean
Initial Thinking Time for 3-(S = −35.5, p < .02) and 5-move (S
= −34.5, p < .02) problems (Figure 2(a)). Interestingly, they
were not observed for 4-move problems, perhaps due to a
trade-off between speed and accuracy, although this is only
speculative. Between errors (akin to perseverative errors) on the
Spatial Working Memory (SWM) task were significantly re-
duced following aripiprazole augmentation for 6-move prob-
lems (S = −33.0, p < .007), and were in the expected direction
for 8-move problems. The Spatial Working Memory Strategy
score, which represents efficiency in completing the working
memory task, also significantly improved following aripipra-
zole augmentation (S = −23.5, p < .04) (lower score = more
efficient use of strategy) (see Figure 2(b)). No significant
changes were observed on measures of attention, visual or ver-
bal learning and memory, or decision making and response
control.
The Relationship between Changes in Depressive
Symptom Severity, Psychosocial Function, and
Executive Function
When the relationship between changes among symptom se-
verity, psychosocial function, and executive function tasks were
evaluated, an interesting pattern of results was observed.
Changes in depressive symptom severity occurred primarily
early in treatment, with the greatest reductions observed be-
tween baseline and Week 3, and smaller additional reductions
occurring between Weeks 3 and 6. In contrast, many of the
psychosocial function measures showed the greatest improve-
(a)
(b)
Figure 2.
Executive Function Changes Following Aripiprazole Augmentation. Mean initial thinking time (in ms)
was significantly decreased following aripiprazole augmentation on the Stockings of Cambridge task
(SOC) for 3- and 5-move problems (top panel). On the spatial working memory task, the number of
errors was significantly reduced on 6-move problems, and the strategy score significantly improved
(bottom panel). *Significant at p < .05; **Significant at p < .01

T. L. GREER ET AL.
Open Access 51
ments in the later weeks of treatment (i.e., between Weeks 3
and 6). There were no significant correlations between depres-
sive severity and executive function measures that improved
with aripiprazole augmentation. Interestingly, the majority of
significant correlations between psychosocial function and chang-
es in executive function occurred in the last three weeks of
treatment, suggesting that cognitive changes are occurring fol-
lowing the greatest reductions in symptom severity and in con-
junction with the greatest changes in psychosocial function (see
Table 3). Although the timing of these changes is not exclu-
sively limited to a specific time interval, these data warrant fur-
ther investigation in a larger sample.
Safety and Tolerability
Four participants who began aripiprazole augmentation dis-
continued treatment due to side effects, which included: aka-
thisia, feeling “spaced out”, dizziness, chest pain, sedation,
weight gain, restlessness and drowsiness. Side effects measured
by the PRISE are reported in Table 4. Adverse effects reported
at 30% or more of study visits include poor concentration, dif-
ficulty sleeping, fatigue, loss of sexual desire, restlessness,
decreased energy, anxiety, headache, and constipation.
Discussion
The results of this study support significant functional im-
provements, in addition to significant reductions in depressive
symptoms, in quality of life, psychosocial function, and execu-
tive functioning following aripiprazole augmentation in MDD.
Table 3.
Significant correlations between change in executive function and change in
psychosocial function.
Week 0 to Week 3
Psychosocial
Measure
SOC Mean
Initial Thinking
Time
(3-moves)
SOC Mean
Initial Thinking
Time
(5-moves)
SWM Strategy
Q-LES-Q
Household Duties −.65
Q-LES-Q Leisure
Time Activities −.57
Q-LES-Q Work −.89
SF-36 Bodily
Pain −.58
Week 3 to Week 6
Psychosocial
Measure
SOC Mean
Initial Thinking
Time
(3-moves)
SOC Mean
Initial Thinking
Time
(5-moves)
SWM Strategy
Q-LES-Q
Physical Health −.68 −.62
Q-LES-Q Work
SF-36 Social
Function −.74
SF-36 Vitality −.66
SF-36 Health
Change −.59
SOC = Stockings of Cambridge; SWM = Spatial Working Memory; Q-LES-Q =
Quality of Life Enjoyment and Satisfaction Questionnaire; SF-36 = Short-Form
Health Survey.
In addition, aripiprazole augmentation was generally well-tol-
erated. We believe the results of this study support further in-
vestigation of the utility of aripiprazole in improving functional
outcomes, including executive function, through a larger, con-
trolled trial.
Table 4.
Adverse effects as measured by the PRISE.
Adverse Effect Percent Frequency
Gastrointestinal
Diarrhea 18.0 20
Constipation 30.6 34
Dry mouth 16.2 18
Nausea/Vomiting 5.4 6
Cardiovascular
Heart palpitation 7.2 8
Dizziness on standing 4.5 5
Chest pain 2.7 3
Skin
Rash 1.8 2
Increased perspiration 18.9 21
Itching 3.6 4
Dry skin 6.3 7
Nervous Sy s t em
Headache 36.9 41
Tremors 9.9 11
Poor coordination 7.2 8
Dizziness 6.3 7
Eyes/Ears
Blurred vision 10.8 12
Ringing in ears 13.5 15
Genital/Urinary
Difficulty urinating 5.4 6
Painful urination 1.8 2
Frequent urination 10.8 12
Menstrual irregularity 4.5 5
Sleep
Difficulty sleeping 49.5 55
Sleeping too much 26.1 29
Sexual Functioning
Loss of sexual desire 46.0 51
Trouble achieving orgasm 9.9 11
Trouble with erection 0.9 1
Other
Anxiety 38.7 43
Poor concentration 59.0 65
General malaise 22.5 25
Restlessness 41.4 46
Fatigue 47.8 53
Decreased energy 39.6 44
Note that occurrences are reported by percent occurrence and frequency across all
observed visits (n = 111), PRISE = Patient Rated Inventory of Side Effects.

T. L. GREER ET AL.
Open Access 52
The study was limited by the fact that it was an open-label
trial in a small sample, and the results should be evaluated in
that context. There are however, strengths in the study design
that are relevant to future examinations of cognitive function in
depression. A major strength of the study was the endorsement
of cognitive complaints as an inclusion criterion. However, it is
true that subjective reports of cognitive deficits do not neces-
sarily translate to objective impairment. It is our belief, how-
ever, that relying solely on objective verification of impairment
at baseline may well miss the opportunity to observe clinically
meaningful improvements in cognitive function. Baseline im-
pairment need not necessarily be one or two standard deviations
below normed scores to be a clinically relevant departure from
an individual’s typical score when they are not depressed. In
this study, participants endorsed impairment at baseline and
showed significant functional improvements following aripip-
razole augmentation. In addition, this study examined the rela-
tionship between changes in cognitive function and psychoso-
cial function. Future studies may benefit from the use of similar
approaches to evaluating cognitive impairment, and more thor-
oughly examining its relationship to psychosocial function.
In addition to supporting possible functional benefits of ari-
piprazole augmentation, the results of this study are both excit-
ing and promising with respect to general evaluation of func-
tional outcomes in MDD for several reasons. First, they support
the need to measure functional outcomes in treatment studies of
MDD so that the impact of treatments on function, and particu-
larly cognitive function, can be evaluated. There have been few
studies conducted that assess the impact of augmentation stra-
tegies on cognitive function in treatment-refractory MDD. Lev-
kowitz et al. (2012) assessed self-rated symptoms using the
Cognitive and Physical Functioning Questionnaire (CPFQ) in
SSRI non-responders who were augmented with S-adenosyl
methionine (SAMe) and found significant improvements in
verbal recall and a trend toward significance in word finding.
Other studies have found marginal cognitive benefits with aug-
mentation approaches such as cholinesterase inhibitors in the
elderly depressed (Reynolds et al., 2011; McDermott & Gray,
2012), but to our knowledge this is one of the first studies ex-
amining objective cognitive performance in a wider age range.
The results of this study also support the use of targeted treat-
ments to address specific symptoms (e.g., executive function
impairments) that may improve the quality of life and func-
tioning of persons with depression. Of great interest is the
finding that changes in symptom severity occurred earlier in the
course of treatment, whereas psychosocial and cognitive
changes were more closely related and occurred later in the
course of treatment. These findings are of course preliminary,
particularly given the short duration of the trial, but they do
indicate the need to better understand the relationship and tim-
ing of changes in these important outcomes to help improve the
treatment of MDD.
Acknowledgements
This research was funded by Bristol-Myers Squibb (Sun-
derajan, PI). TLG has received research funding from NARSAD
and consulting fees from H. Lundbeck A/S. PS has also re-
ceived research support from Lilly USA, LLC and Takeda
Pharmaceuticals North America, Inc. BDG has no disclosures
to report.
MHT reports that he is or has been an advisor/consultant to,
or on the Speakers’ Bureaus for: Abbott Laboratories, Inc.,
Abdi Ibrahim, Akzo (Organon Pharmaceuticals Inc.), Alkermes,
AstraZeneca, Axon Advisors, Bristol-Myers Squibb Company,
Cephalon, Inc., Cerecor, Concert Pharmaceuticals, Inc., Eli
Lilly & Company, Evotec, Fabre Kramer Pharmaceuticals, Inc.,
Forest Pharmaceuticals, GlaxoSmithKline, Janssen Global Ser-
vices, LLC, Janssen Pharmaceutica Products, LP, Johnson &
Johnson PRD, Libby, Lundbeck, Meade Johnson, MedAvante,
Medtronic, Merck, Mitsubishi Tanabe Pharma Development
America, Inc., Naurex, Neuronetics, Otsuka Pharmaceuticals,
Pamlab, Parke-Davis Pharmaceuticals, Inc., Pfizer Inc., Pgx-
Health, Phoenix Marketing Solutions, Rexahn Pharmaceuticals,
Ridge Diagnostics, Roche Products Ltd., Sepracor, SHIRE
Development, Sierra, SK Life and Science, Sunovion, Takeda,
Tal Medical/Puretech Venture, Targacept, Transcept, Vantage-
Point, Vivus, and Wyeth-Ayerst Laboratories. In addition, he
has received research support from: Agency for Healthcare
Research and Quality (AHRQ), Corcept Therapeutics, Inc., Cy-
beronics, Inc., National Alliance for Research in Schizophrenia
and Depression, National Institute of Mental Health, National
Institute on Drug Abuse, Novartis, Pharmacia & Upjohn, Pre-
dix Pharmaceuticals (Epix), and Solvay Pharmaceuticals, Inc.
We are especially grateful to our participants. We also would
like to thank Carol A. Tamminga, M.D., Communities Founda-
tion of Texas, Inc. Chair in Brain Science, and Chair, Depart-
ment of Psychiatry, University of Texas Southwestern Medical
Center for administrative support, and Kolette Ring for assis-
tance with manuscript preparation.
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