Cognitive and Psychosocial Improvements Following Aripiprazole Augmentation of SSRI Antidepressant Therapy in Treatment Refractory Depression : A Pilot Study

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. Participants 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 specifically evaluate functional outcomes in MDD.


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 burdensome disease in high-income countries, and second-most overall, 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 contribute 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 memory, 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 disorders (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 management 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 individuals (Greer et al., 2010).Some potential treatments for cognitive 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 antidepressants for MDD.When added to ongoing antidepressant treatment that is not fully resolving depressive symptoms, aripiprazole increases the likelihood of remission (Berman et al., 2009;Nelson et al., 2012).It is well-tolerated, even after longterm (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 functional 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 augmentation was associated with significantly greater reductions in mean SDS scores, as well as with the individual items measuring 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 Montgomery-Asberg Depression Rating Scale (MADRS) and the Inventory for Depressive Symptomatology, Self-Report (IDS-SR).They did not find that aripiprazole augmentation was superior to placebo augmentation on concentration symptoms as measured by the items addressing that symptom on either scale; however, it is not clear how many participants endorsed concentration 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 serotonergic systems.It affects serotonergic activity via mechanisms that are identical to agents that have been established as effective antidepressants.Specifically, aripiprazole is a partial agonist at 5-HT 1A receptors and an antagonist at 5-HT 2 receptors (Burris et al., 2002).In comparison to other commonly used atypical or typical antipsychotic agents, aripiprazole has a higher affinity for 5-HT 1A receptors, and has an affinity for 5-HT 2 receptors that is higher than or comparable to most other antipsychotics agents (surpassed only by risperidone and ziprasidone) (Burris et al., 2002;Bymaster et al., 1996;Seeger et al., 1995).Aripiprazole is also a partial agonist of both D 2 and D 3 dopaminergic receptors (Tadori et al., 2008).D 2 and D 3 agonism 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 depressed individuals who endorsed difficulties with concentration and decision-making that were significant enough to disrupt their functioning.This study was conducted to gather preliminary data for assessment of the following: 1) the effect of aripiprazole augmentation on depressive symptom severity, psychosocial function and cognitive function, and 2) the relationship 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.

Participants
The study protocol and informed consent form were approved by the University of Texas Southwestern Medical Center 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, (HRSD 17 ) score of 14 or greater or a Clinical Global Impression Scale-Severity (CGI-S) score of 3 or greater.Participants had to report difficulties with concentration or cognition and score 2 or greater on the 30-item Inventory for Depressive Symptomatology-Clinician-Rated (IDS-C 30 ) 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 compulsive disorder, alcohol or substance abuse or dependence within the last 6 months, or high suicide risk), or concomitant pharmacological 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 assessment battery that included measures of depressive symptoms, psychosocial function, and cognitive function, as described below.

Assessment of Depressive Symptoms
The HRSD 17 and IDS Self-Report (IDS-SR 30 ) were used to assess severity of depressive symptoms at screening, baseline, and weekly thereafter.The HRSD 17 (Hamilton, 1960) is a clinician-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-SR 30 (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 Physical.The Quality of Life Enjoyment and Satisfaction Questionnaire, General Activities (Q-LES-Q) (Endicott & Nee, 1993) was used to measure satisfaction and enjoyment in various 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 = .70to .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 function was assessed via the Inventory for Depressive Symptomatology item "Concentration and Decision Making".The Cambridge Neuropsychological Test Automated Battery (CANTAB) (Cambridge Cognition Limited, 2004) was used to assess preand post-treatment cognitive function.CANTAB is a comprehensive 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 depressed patients and healthy controls.The tasks selected represented each of the following domains: Attention, Visual Memory, 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 Research 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 simultaneously with the sample or after a brief delay; Paired Associates 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 memory, with the ability for assessment of perseverative (redundant) 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 planning; 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 Recognition Memory (VRM)-a measure of immediate and delayed verbal recall and recognition.
Each task can generate multiple outcome measures (e.g., percent 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 contraindicated due to adverse effects.Participants met with a study psychiatrist on a weekly basis during aripiprazole augmentation 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 impairment 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 depressive 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 distributions 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 function 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 measures.
Completion of the study was required for analyses since cognitive data were obtained only at pre-and post-treatment timepoints.

Results
All participants provided written informed consent.Twenty-

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 six participants were screened for participation, and nine participants were found to be ineligible for the following reasons: presence of significant comorbid medical condition or abnormal laboratory values (4), presence of other psychiatric disorder or severity of symptoms (2), declined further participation (2), and prohibited concomitant medication (1).Seventeen participants began augmentation treatment with aripiprazole.Thirteen participants completed all six weeks of aripiprazole augmentation and thus were included in the analyses.Baseline demographic 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%) responded, defined by a 50% or greater reduction in HRSD score.Seven (41%) remitted, as defined by achieving HRSD score of 7 or less.

Cognitive Function
Significant changes in cognitive function were observed on measures of executive function.Significant changes on difference 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 reduced following aripiprazole augmentation for 6-move problems (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 aripiprazole 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 verbal 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 severity, 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 between 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- 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 < .01ments in the later weeks of treatment (i.e., between Weeks 3 and 6).There were no significant correlations between depressive severity and executive function measures that improved with aripiprazole augmentation.Interestingly, the majority of significant correlations between psychosocial function and changes in executive function occurred in the last three weeks of treatment, suggesting that cognitive changes are occurring following the greatest reductions in symptom severity and in conjunction with the greatest changes in psychosocial function (see Table 3).Although the timing of these changes is not exclusively limited to a specific time interval, these data warrant further investigation in a larger sample.

Safety and Tolerability
Four participants who began aripiprazole augmentation discontinued treatment due to side effects, which included: akathisia, 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, difficulty sleeping, fatigue, loss of sexual desire, restlessness, decreased energy, anxiety, headache, and constipation.

Discussion
The results of this study support significant functional improvements, in addition to significant reductions in depressive symptoms, in quality of life, psychosocial function, and executive functioning following aripiprazole augmentation in MDD.In addition, aripiprazole augmentation was generally well-tolerated.We believe the results of this study support further investigation of the utility of aripiprazole in improving functional outcomes, including executive function, through a larger, controlled trial.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 necessarily translate to objective impairment.It is our belief, however, that relying solely on objective verification of impairment at baseline may well miss the opportunity to observe clinically meaningful improvements in cognitive function.Baseline impairment 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 aripiprazole augmentation.In addition, this study examined the relationship between changes in cognitive function and psychosocial function.Future studies may benefit from the use of similar approaches to evaluating cognitive impairment, and more thoroughly examining its relationship to psychosocial function.
In addition to supporting possible functional benefits of aripiprazole augmentation, the results of this study are both exciting and promising with respect to general evaluation of functional 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 particularly cognitive function, can be evaluated.There have been few studies conducted that assess the impact of augmentation strategies on cognitive function in treatment-refractory MDD.Levkowitz 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 augmentation 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 examining objective cognitive performance in a wider age range.The results of this study also support the use of targeted treatments to address specific symptoms (e.g., executive function impairments) that may improve the quality of life and functioning 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 timing of changes in these important outcomes to help improve the treatment of MDD.
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

Table 1 .
Description of cognitive function outcome measures.

Table 3 .
Significant correlations between change in executive function and change in psychosocial function.
SOC = Stockings of Cambridge; SWM = Spatial Working Memory; Q-LES-Q = Quality of Life Enjoyment and Satisfaction Questionnaire; SF-36 = Short-Form Health Survey.

Table 4 .
Adverse effects as measured by the PRISE.
Note that occurrences are reported by percent occurrence and frequency across all observed visits (n = 111), PRISE = Patient Rated Inventory of Side Effects.