Neuropsychopharmacology (2012) 38, S314–S446
`& 2012 American College of Neuropsychopharmacology All rights reserved 0893-133X/12
`
`S314
`
`www.neuropsychopharmacology.org
`
`Poster Session III
`Wednesday, December 05, 2012
`
`W2. Treatment with Adjunctive Aripiprazole Results in
`Significant Improvement Compared with Continued
`Antidepressant Monotherapy in Patients with Mild, Moderate,
`and Severe Major Depressive Disorder
`J Craig. Nelson*, Thomas D. Stewart, Ainslie Hatch,
`Kimberly Largay, Elizabeth E. Bellochio, Sabrina V. Marler,
`Ross A. Baker, John Sheehan, Robert M. Berman
`
`University of California, San Francisco, California
`
`Background: The severity of a patient’s depressive symptoms
`may inform treatment decisions. However, current
`treatment
`guidelines are based on trial data that group patients of varying
`degrees of severity together. To better understand the appropriate
`patient for adjunctive aripiprazole in major depressive disorder
`(MDD),
`this post-hoc analysis pooled data from 3 similar,
`randomized trials,1,2 and stratified patients based on published
`severity cut-offs on the Montgomery A˚ sberg Depression Rating
`Scale (MADRS).3
`Methods: These trials enrolled patients with an inadequate
`response to 1-3 trials of antidepressant therapy (ADT). Each study
`had an 8-week prospective ADT phase (Phase B), followed by a
`6-week randomized phase (Phase C) of adjunctive aripiprazole
`versus continued antidepressant monotherapy + placebo for
`patients with an inadequate response during the prospective phase.
`Inadequate response to ADT monotherapy was defined as o50%
`reduction in the 17-item Hamilton Rating Scale for Depression
`(HAM-D-17) total score, HAM-D-17 total score X14, and Clinical
`Global Impressions-Improvement (CGI-I) score X3. For this post-
`hoc analysis, patients were stratified at the beginning of Phase C by
`MADRS total score into 3 groups: mild (MADRS total score p24),
`moderate (MADRS total score¼ 25-30), and severe (MADRS total
`score X31). During Phase C, aripiprazole was flexibly dosed with a
`target of 10 mg/day. Patients were initiated at 5 mg/day (could
`decrease to 2 mg/day for tolerability) and increased to 10 mg/day
`(could decrease to 5 mg/day for tolerability) at the end of Week 1;
`the maximum dose was 20 mg/day. Change in MADRS total score
`for adjunctive aripiprazole and adjunctive placebo was assessed at
`the end of 6 weeks using last observation carried forward (LOCF).
`Results: Baseline demographics across the three groups appeared
`similar. At the beginning of Phase C, in the aripiprazole group, 224
`(41%), 206 (38%), and 110 (20%) patients were considered mild,
`moderate, or severe, respectively; in the placebo group, it was
`191
`(36%),
`179 (34%), and 155 (30%) patients, respectively.
`At the end of 6 weeks, mean changes in MADRS total score
`between aripiprazole and placebo were significantly different in
`all three severity groups: mild 7.9 aripiprazole vs. 5.4 placebo
`(P¼ 0.0005); moderate 9.5 aripiprazole vs. 6.3 placebo
`(P¼ 0.0001);
`severe 11.9
`vs. 7.4 placebo
`aripiprazole
`(P¼ 0.0001). Statistically significantly differences between aripi-
`prazole and placebo first appeared at Week 1 (mild or severe) or
`Week 2 (moderate). In all three groups, the endpoint effect size of
`aripiprazole treatment was moderate (0.334-0.483). Similarly, mean
`percent improvement in MADRS total score between aripiprazole
`and placebo were significantly different in all three severity groups:
`mild -38% aripiprazole vs. -26% placebo (P¼ 0.0008); moderate -
`35% aripiprazole vs. -23% placebo (P¼ 0.0001); severe -35%
`aripiprazole vs.¼ 22% placebo (P¼ 0.0002). Adjunctive aripipra-
`zole was well tolerated across the severity groups, with no trends in
`the proportion of patients reporting an adverse event (AE) based
`on severity; the most common AEs in the aripiprazole-treated
`groups were akathisia and restlessness.
`
`ACNP 51st Annual Conference
`
`In this pooled analysis, adjunctive aripiprazole
`Conclusions:
`resulted in significantly greater symptom improvement
`than
`placebo regardless of baseline severity. Change scores appeared
`greatest in the severe group but this may reflect the truncated
`range in the mild group. The greater response with adjunctive
`aripiprazole demonstrates the utility of this strategy to manage
`depression in a wide spectrum of patients.
`References 1. Thase ME, et al. Examning the efficacy of adjunctive
`aripiprazole in major depressive disorder: a pooled analysis of 2
`studies. Prim Care Companion J Clin Psychiatry. 2008;10:440-7.2.
`Berman RM, et al. Aripiprazole augmentation in major depressive
`disorder: a double-blind, placebo-controlled study in patients with
`inadequate response to antidepressants. CNS Spectr. 2009;14:
`197-206.3. Kearns NP, et al. A comparison of depression rating
`scales. Brit J Psychiat. 1982;141:45-9.
`Keywords: aripiprazole, depression, antidepressants, MADRS,
`treatment
`Disclosure: J. Nelson, Part 1: Honoraria from Eli Lilly Global,
`Lundbeck, Otsuka Asia, Schering Plough/Merck (Asia); consultant
`for Bristol-Myers Squibb, Cenestra Health, Corcept, Covidien, Eli
`Lilly, Forest, Lundbeck, Medtronics, Merck, Mylan (Dey Pharma),
`Orexigen, Otsuka, Pfizer, Sunovion, served on advisory boards for
`Avanir, Bristol-Myers Squibb, Eli Lilly, Labopharm, Mylan (Dey
`Pharma), and Otsuka, Part 2: Honoraria from Eli Lilly Global,
`Lundbeck, Otsuka Asia, Schering Plough/Merck (Asia); consultant
`for Bristol-Myers Squibb, Cenestra Health, Corcept, Covidien, Eli
`Lilly, Forest, Lundbeck, Medtronics, Merck, Mylan (Dey Pharma),
`Orexigen, Otsuka, Pfizer, Sunovion, served on advisory boards for
`Avanir, Bristol-Myers Squibb, Eli Lilly, Labopharm, Mylan (Dey
`Pharma), and Otsuka, Part 3: n/a, Part 4: n/a; T. Stewart, Part 1:
`Speaker for Bristol-Myers Squibb Co., and Otsuka Pharmaceutical
`Co., Ltd.; A. Hatch, Part 1: Employee of Otsuka Pharmaceutical
`Development & Commercialization, Inc., Part 2: Employee of
`Otsuka Pharmaceutical Development & Commercialization, Inc.;
`K. Largay, Part 1: Employee of Otsuka Pharmaceutical Develop-
`ment & Commercialization, Inc., Part 2: Employee of Otsuka
`Pharmaceutical Development & Commercialization,
`Inc.; E.
`Bellochio, Part 1: Employee of Bristol-Myers Squibb Co., Part 2:
`Employee of Bristol-Myers Squibb Co., Part 3: Employee of Bristol-
`Myers Squibb Co.; S. Marler, Part 1: Employee of Bristol-Myers
`Squibb Co., Part 2: Employee of Bristol-Myers Squibb Co., Part 3:
`Employee of Bristol-Myers Squibb Co.; R. Baker, Part 1: Employee
`of Otsuka Pharmaceutical Development and Commercialization,
`Inc, Part 2: Employee of Otsuka Pharmaceutical Development and
`Commercialization, Inc, Part 3: Employee of Otsuka Pharmaceu-
`tical Development and Commercialization, Inc; J. Sheehan, Part 1:
`Employee of Bristol-Myers Squibb Co., Part 2: Employee of Bristol-
`Myers Squibb Co., Part 3: Employee of Bristol-Myers Squibb Co.;
`R. Berman, Part 1: Employee of Bristol-Myers Squibb Co., Part 2:
`Employee of Bristol-Myers Squibb Co.
`
`W3. Genomic Predictors of Response to Antidepressant
`Treatment in Geriatric Depression Using Genome-wide
`Expression Analyses: A Pilot Study
`Helen Lavretsky*, Ascia Eskin, Stanley Nelson, Steve Cole
`
`UCLA, Los Angeles, California
`
`Background: Depression and antidepressant response are asso-
`ciated with leukocyte gene transcriptional alterations. The present
`pilot study examined immune cell gene expression with anti-
`depressant treatment in geriatric depression.
`Methods: Genome-wide transcriptional profiles were collected
`from peripheral blood leukocytes sampled at baseline and 16-week
`follow-up from 37 older adults with major depression who were
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`Abstracts
`
`S315
`
`randomized to methylphenidate + citalopram; citalopram + place-
`bo; or methylphenidate + placebo. Methylphenidate dose ranged
`between 10-40 mg per day, and citalopram dose was 20-40 mg per
`day. Genome-wide transcriptional profiling was carried out in the
`peripheral blood mononuclear cell samples obtained at baseline
`and post-intervention. Promoter-based bioinformatics analyses
`tested the hypothesis that observed transcriptional alterations were
`structured by transcription factors implicated in dopaminergic,
`serotonergic, and neuroplastic pathways.
`Results: 25 responder and 12 non-responders gene expression
`profiles were analyzedIn the analyses of covariance controlling for
`treatment group, 2 gene transcripts showed systematic up-
`regulation in non-responders at baseline. Up-regulated genes at
`baseline in non-responders compared to non-responders included
`1) CA1 carbonic anhydrase gene on chromosome 8 involved in
`reversible hydration of CO2 and respiratory function (fold change
`2.54; P¼ 0.03); 2) SNCA -alpha-synuclein gene implicated in
`Parkinson’s disease that binds to dopamine transporter (fold
`change 2.1; P¼ 0.03). Additionally, promoter-based bioinformatic
`analysis of genes found to be upregulated by 1.2-fold indicated a
`reduction in CREB activity in responders versus non-responders
`over time in the entire sample and in the subgroup taking
`methylphenidate and placebo (both po.0001, or Bonferroni-
`corrected po.05).
`Conclusions: The present results suggest a unique transcriptional
`signature in responders and non-responders to antidepressant
`treatment in the dopaminergic and metabolic pathways important
`for neurolplasticity and brain aging. Response to treatment in the
`overall sample and to methylphenidate was associated with a
`reduction in CREB activity in responders versus non-responders.
`Our results are novel
`in identifying potential biomarkers of
`response/nonresponse to an antidepressant treatment in geriatric
`depression, but will need to be replicated in larger samples with
`the use of additional specific biomarkers of
`the identified
`pathways.
`Keywords: Genomic, microarrays, predicotrs of
`response, antidperessant, gelriatric depression
`Disclosure: H. Lavretsky, Part 1: Research grants from Forest
`Research Institute; Consulting fee from Lilly, Dey Pharmacuetical,
`Part 4: Forest Research Institute; A. Eskin, Nothing to Disclose; S.
`Nelson, Nothing to Disclose; S. Cole, Nothing to Disclose.
`
`treatment
`
`W4. The Acetylcholinesterase Inhibitor, Rivastigmine, but not
`Huperzine A, Improves Verbal Learning/Episodic Memory and
`Working Memory in Cocaine-dependent Volunteers
`James Joseph. Mahoney*, Ari Kalechstein, Thomas Newton,
`Ryan Bennett, Nicholas Arnoudse, Richard De La Garza
`
`Baylor College of Medicine, Pearland, Texas
`
`Background: Long-term, high-dose cocaine use is a risk factor for
`the onset of neurocognitive impairment in humans. In a recent
`meta-analytic review of 15 studies that included 586 matched
`controls and 481 abstinent cocaine users, effect sizes of moderate
`or greater magnitude for attention, episodic memory, and working
`memory were reported (Jovanovski, 2005). These neurocognitive
`impairments have important implications with respect to day-to-
`day functioning; for example, the presence of cocaine-associated
`neurocognitive impairment
`is associated with poor treatment
`retention/increased treatment dropout. Not surprising, cocaine-
`associated neurocognitive impairment has been identified as an
`important target of treatment, and medications such as modafinil
`have demonstrated an indication vis-a`-vis improvement on
`measures of working memory. Thus, given that cocaineFasso-
`ciated neurocognitive impairment
`is potentially amenable to
`treatment, this study sought to determine whether the acetylcho-
`linesterase inhibitors rivastigmine or huperzine A could improve
`neurocognitive performance in cocaine-dependent individuals.
`
`Methods: Seventy two cocaine-dependent individuals who were
`not seeking treatment at the time of enrollment in the study were
`randomly assigned to receive placebo (n¼ 15), rivastigmine 3 mg
`(n¼ 14), rivastigmine 6 mg (n¼ 14), huperzine A 0.4 mg (n¼ 15),
`or huperzine A 0.8 mg (n¼ 14). Urinanalysis was used to confirm
`abstinence from cocaine on the day of admission and during the
`next 7 days. The baseline neurocognitive assessment, which
`included measures of attention/information processing (as mea-
`sured by the Continuous Performance Task), verbal
`learning
`episodic memory (as measured by the Hopkins Verbal Learning
`Test), and working memory (as measured by the Dual N-Back
`Task), was conducted immediately after the washout phase and
`prior to the administration of study medication (Day 0). The
`follow-up assessment was conducted on Day 8 after participants
`had received rivastigmine, huperzine A, or placebo for seven days
`(Day 2-8).
`Results: Enrolled participants were primarily African-American,
`B41 years old, had B12 years of education, used cocaine for B16
`years and B17 out of the last 30 days, and used B2 grams of
`cocaine per day via the smoked route of administration.
`Rivastigmine administration (6 mg) significantly improved per-
`formance on two measures of working memory span (mean n-back
`span, maximum n-back span) and improved performance on a
`learning and memory task (HVLT total recall). Those
`verbal
`participants randomized to 6 mg rivastigmine had significantly
`higher mean n-back span (1.91±.12; Mean±SEM) when compared
`to those randomized to placebo (1.55±0.12; po0.02). In addition,
`those participants randomized to 6 mg rivastigmine had signifi-
`cantly higher max n-back span (2.64±0.19) when compared to
`those randomized to placebo (2.07±.18; po0.03). Furthermore,
`those participants
`randomized to 6 mg
`rivastigmine had
`significantly higher scaled total verbal
`learning HVLT scores
`(42.14±2.45) when
`compared
`to
`those
`randomized
`to
`placebo (31.73±2.37; po0.001). There were no differences
`between rivastigmine and placebo groups on measures of
`sustained
`attention/information
`processing
`and
`huperzine
`A did not modulate performance on measures of information
`processing speed, verbal learning/ episodic memory, or working
`memory.
`Conclusions: This study provides additional data showing that
`cocaine-associated neurocognitive impairment,
`in a sample of
`long-term, high-dose cocaine users, can be remediated. Addition-
`ally, while this confirms that working memory impairments are
`amenable to treatment, this is to our knowledge, the first study to
`show that cocaine-associated memory impairment can be treated.
`These effects are likely relevant
`in the treatment of cocaine
`dependence, in which the remediation of impaired verbal learning,
`episodic, and working memory may be associated with improved
`treatment outcomes.
`Keywords: cocaine; acetylcholinesterase inhibitor; neurocognition;
`verbal learning; working memory
`Disclosure: J. Mahoney, Nothing to Disclose; A. Kalechstein,
`Nothing to Disclose; T. Newton, Nothing to Disclose; R. Bennett,
`Nothing to Disclose; N. Arnoudse, Nothing to Disclose; R. De La
`Garza, Part
`I
`served as an expert witness
`for Pfizer
`1:
`(the pharmaceutical company that makes varenicline) in the
`Chantix litigation, I was paid on an hourly basis to write an expert
`report and opinions on published articles by other scientists
`with regard to the safety of Chantix administration in humans.
`There is no potential interest affected with regard to the data
`presented in this abstract, Part 2: DLA Piper (law firm representing
`Pfizer), Part 3: I served as an expert witness for Pfizer (the
`pharmaceutical company that makes varenicline) in the Chantix
`litigation, I was paid on an hourly basis to write an expert report
`and opinions on published articles by other scientists with regard
`to the safety of Chantix administration in humans. There is no
`potential interest affected with regard to the data presented in this
`abstract.
`
`ACNP 51st Annual Conference
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`S316
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`W5. Treatment of Depression with Botulinum Toxin A:
`A Randomized, Double-blind, Placebo Controlled Trial
`Eric Finzi*, Norman Rosenthal
`
`Abstracts
`
`Chevy Chase Cosmetic Center, Chevy Chase, Maryland
`
`Background: In spite of advances in our understanding and
`treatment of major depressive disorder (MDD), many patients fail
`to achieve remission. Recently,
`it has been proposed that
`inhibition of frowning could be used as a treatment for MDD
`(Finzi et al., 2006). Preliminary studies have suggested that
`botulinum toxin treatment of frown muscles may help depression
`(Finzi et al., 2006, Wollmer et al., 2012). The corrugator (frown)
`muscle plays an essential role in the facial expressions of anger and
`sadness. Charles Darwin first suggested that muscle contractions
`involved in the formation of
`facial expressions contribute to
`emotional states and mood; William James elaborated on this
`concept, which has been confirmed experimentally, and is now
`known as the facial feedback hypothesis. Darwin also recognized
`that severely depressed individuals show corrugator muscle
`overactivity, which may result in the ‘‘omega sign.’’ Botulinum
`toxin (BT) reversibly inhibits muscle contraction. When injected
`into the glabellar region, BT reversibly inhibits frowning for about
`three months. We have conducted a randomized, double-blind,
`placebo controlled trial of BT injection into the glabellar region as
`a treatment for MDD.
`Methods: The study was IRB approved, and informed consent was
`given by all subjects. Male or female outpatients aged 18 to 65
`years, with MDD, as diagnosed by the Structured Clinical Interview
`for Axis I DSM-IV Disorders (SCID), were eligible. Subjects were
`required to have a Montgomery-Asberg (MADRS) score X 26 and
`a Clinical Global Impression – Severity (CGI) score X 4 at
`screening Eligible subjects were randomly assigned at screening to
`receive either onabotulinumtoxinA(OBA) (Botox Cosmetic, Aller-
`gan) or placebo(PLB) (0.9%NaCl) injections in the glabellar
`region(Finzi et al., 2006). Women received 29 U of OBA and
`men, 40 U. All patients were assessed at randomization and after 3
`and 6 weeks with the MADRS, Beck Depression Inventory II (BDI)
`and CGI. The primary outcome measure was response to
`treatment, as defined as a X 50% decrease in MADRS score.
`Remission was defined as a MADRS score of 10 or lower along with
`a X50% decrease in score. Secondary outcomes were response to
`treatment in scores on BDI and CGI. Subjects at rest and maximal
`frowns were assessed photographically at the beginning and end of
`the study.
`Results: 121 subjects were screened, of whom 84 subjects were
`randomized: 41 to OBA and 43 to placebo. Eight patients were
`excluded (4 patients in the OBA group for withdrawal of consent,
`and two in each group for protocol violations). One OBA subject
`was lost to follow-up after injection. 33 subjects in the OBA group
`and 41 in the placebo group completed all three visits. The two
`groups did not differ significantly on any of the demographic or
`clinical baseline variables. 91% of the OBA and 80% of the PLB
`subjects suffered from recurrent depression. The average number
`of antidepressants tried during subject lifetimes, were 2.2 for OBA,
`and 1.8 for PLB, and the mean duration of the current depressive
`episode was 27.9 months. As for the primary end point, MADRS
`scores at the six week visit versus baseline, there was a significant
`improvement in the OBA group compared to the PLB group; there
`was a 47.0% reduction in MADRS scores for OBA subjects, versus a
`20.6% reduction for PLB (student’s t test, po0.0004). The OBA
`group showed a significant clinical improvement in depression,
`compared to the PLB group, over time, as measured by MADRS
`f¼ 9.7, po0.0028,
`score, (ANOVA,
`two-tailed); BDI-II score,
`(ANOVA, f¼ 5.7, po0.019, two-tailed.); and CGI score (ANOVA,
`f¼ 15.3, po0.0002, two-tailed.). The response rate for MADRS was
`51.5% vs. 14.6%; po0.0009 Fisher’s exact test. The remission rate,
`as judged by MADRS, was significantly higher in the OBA group,
`
`ACNP 51st Annual Conference
`
`27.3%, than in the PLB group, 7.3%, po0.027, Fisher’s exact test. A
`decrease in the maximal ability to frown at 6 weeks (among all
`subjects) was correlated with MADRS response; po0.01; Spearman
`coefficient. In the OBA group, there was a trend towards greater
`response (X50% decrease in MADRS score) with increasing
`baseline frown (N.S., po0.07).
`randomized, double-blind
`first
`Conclusions: This
`is
`the
`trial
`to show that a single
`and placebo -controlled clinical
`treatment of the glabellar region with OBA induces a strong and
`sustained alleviation of symptoms in a broadly defined group of
`people with MDD. The results are consistent with those of
`our earlier pilot study (Finzi et al.) and the prior smaller controlled
`study of BT in patients with refractory depression. Our study is
`also the first
`to show that subjects treated with OBA went
`into remission at a significantly higher rate than placebo subjects.
`The mechanism of action of OBA in helping depression is
`unknown, but our results support the facial feedback hypothesis
`and suggest that it can be utilized therapeutically. The results also
`support the concept of emotional proprioception (Finzi, 2013)
`whereby the brain continuously monitors the relative valence of
`salient facial expressions, which may be an important influence on
`mood.
`Keywords: botulinum toxin depression clinical trial
`Disclosure: E. Finzi, Part 4: Dr Finzi has received a use patent to
`treat major depression with botulinum toxin; N. Rosenthal,
`Nothing to Disclose
`
`W6. Adjunctive Aripiprazole More Than Doubles the Rate of
`Early and Sustained Response across Multiple Measures in
`Patients with MDD Who Have an Inadequate Response to
`Antidepressant Monotherapy
`Daniel E. Casey*, Kimberly Laubmeier, Eudicone James,
`Ronald N. Marcus, Ross A. Baker, John Sheehan,
`Robert M. Berman
`
`Oregon Health and Science University, Portland, Oregon
`
`Background: Medications with rapid antidepressant effects ad-
`dress an unmet need in major depressive disorder (MDD), as it can
`take several weeks to determine if a given antidepressant will be
`effective for an individual patient. However, a rapid, transient
`effect alone does not address patients’ longer-term needs. There-
`fore, we evaluated the early and sustained antidepressant effects of
`adjunctive aripiprazole in MDD. Early and sustained response
`(ESusR) is a particularly rigorous measure of efficacy because
`patients must respond early and at all subsequent time points. This
`post-hoc analysis investigated ESusR using both measures of
`symptoms
`(Montgomery Asberg Depression Rating
`Scale
`[MADRS]), total clinical progress from baseline (Clinical Global
`Impression-Improvement scale [CGI-I]) and a measure of clinical
`state versus other patients with depression (CGI-Severity scale
`[CGI-S]).
`Methods: This pooled analysis of 3 similar studies,1,2 enrolled
`patients with an inadequate response to 1-3 trials of antidepressant
`therapy (ADT). Each study had an 8-week prospective ADT phase
`(Phase B),
`then a 6-week randomized phase of adjunctive
`aripiprazole vs. adjunctive placebo (Phase C). In this analysis,
`ESusR was defined as a patient who had a response by one of 3
`measures during Phase C (X50% improvement in MADRS total
`score; CGI-I or CGI-S scores of 1-2) at Week 2 and sustained that
`response at all subsequent visits (Weeks 3, 4, 5, and 6). In addition,
`because the literature presents inconsistent cut-offs for response
`on the CGI-S, we determined the most appropriate definition in
`this population.
`Results: Among Week 2 MADRS Responders, the median and
`mode CGI-S scores at Week 2 were 2 (borderline mentally ill) for
`both adjunctive aripiprazole (n¼ 88) and adjunctive placebo
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`(n¼ 42), while the median and mode CGI-S scores among
`(n¼ 299)
`Week 2
`adjunctive
`aripiprazole
`and adjunctive
`placebo Non-responders (n¼ 345) were 4 (moderately ill). How-
`ever, among Week 2 Responders and Non-Responders the
`distribution of CGI-S scores significantly differed between the
`(po0.0001) and
`aripiprazole and placebo treatment arms
`appeared to favor aripiprazole. The rates of ESusR by MADRS in
`the adjunctive aripiprazole and adjunctive placebo groups were
`11.6% (45/387) and 5.4% (21/387), respectively (P¼ 0.002; relative
`risk [RR]¼ 2.2, 95% CI: 1.3, 3.5). Rates of ESusR by CGI-I in the
`adjunctive aripiprazole and placebo groups were 30.9% (120/389)
`and 15.3% (59/386), respectively (Po0.0001; RR¼ 2.0, 95% CI: 1.5,
`2.7). Rates of ESusR by CGI-S in the adjunctive aripiprazole and
`placebo groups were 13.6% (53/390) and 5.1% (20/389), respectively
`(Po0.0001; RR¼ 2.6, 95% CI: 1.6, 4.3). Overall, 31.3% (121/386) of
`patients receiving aripiprazole responded by at least one measure
`of EsusR compared with 15.6% (60/384) of patients receiving
`placebo.
`Conclusions: In this MDD population who failed previous ADT,
`a CGI-S cut-off of 2 constituted the most appropriate definition
`of response on this scale. The distribution of CGI-S scores
`among Week 2 responders appeared to favor aripiprazole.
`ESusR was demonstrated with adjunctive aripiprazole at a rate
`more
`than
`double
`compared with ADT monotherapy
`using a symptom scale and 2 global
`response measures.
`As expected,
`the response cut-off of MADRS improvement
`X50% was similar to a CGI-S score of 1-2. Both definitions
`appeared to be a more rigorous response definition than CGI-I 1-2.
`The magnitude of treatment effect across the three measures was
`similar. These similar results across three scales suggest aripipra-
`zole reliably and robustly increases the proportion of patients who
`achieve ESusR.
`References: 1. Thase ME, et al: Examining the efficacy of adjunctive
`aripiprazole in major depressive disorder: a pooled analysis of 2
`studies. Prim Care Companion J Clin Psychiatry. 2008;10:440-7.
`2. Berman RM, et al: Aripiprazole augmentation in major
`depressive disorder: a double-blind, placebo-controlled study in
`patients with inadequate response to antidepressants. CNS Spectr.
`2009; 14:197-206.
`Keywords: Aripiprazole, Depression, Response, Antidepressant,
`Clinical trial
`Disclosure: D. Casey, Part 1: Consultant for Abbott Laboratories,
`Bristol-Myers Squibb, Dainippon Sumitomo Pharmaceuticals,
`Genentech,
`Janssen Pharmaceuticals, Merck, and Pfizer Inc.,
`Speakers’ bureau for Abbott Laboratories, Bristol-Myers Squibb,
`Janssen Pharmaceuticals, Merck and Pfizer Inc., Part 2: Consultant
`for Abbott Laboratories, Bristol-Myers Squibb, Dainippon Sumi-
`tomo Pharmaceuticals, Genentech,
`Janssen Pharmaceuticals,
`Merck, and Pfizer Inc., Speakers’ bureau for Abbott Laboratories,
`Bristol-Myers Squibb, Janssen Pharmaceuticals, Merck and Pfizer
`Inc., Part 3: Consultant for Abbott Laboratories, Bristol-Myers
`Squibb, Dainippon Sumitomo Pharmaceuticals, Genentech, Jans-
`sen Pharmaceuticals, Merck, and Pfizer Inc., Speakers’ bureau for
`Abbott Laboratories, Bristol-Myers Squibb, Janssen Pharmaceu-
`ticals, Merck and Pfizer Inc.; K. Laubmeier, Part 1: Employee of
`Otsuka Pharmaceutical Development & Commercialization, Inc.,
`Part 2: Employee of Otsuka Pharmaceutical Development &
`Commercialization, Inc.; E. James, Part 1: Employee of Bristol-
`Myers Squibb Co., Part 2: Employee of Bristol-Myers Squibb Co.;
`R. Marcus, Part 1: Employee of Bristol-Myers Squibb Co., Part 2:
`Employee of Bristol-Myers Squibb Co.; R. Baker, Part 1: Employee
`of Otsuka Pharmaceutical Development & Commercialization, Inc.,
`Part 2: Employee of Otsuka Pharmaceutical Development &
`Commercialization, Inc.; J. Sheehan, Part 1: Employee of Bristol-
`Myers Squibb Co., Part 2: Employee of Bristol-Myers Squibb Co.;
`R. Berman, Part 1: Employee of Bristol-Myers Squibb Co., Part 2:
`Employee of Bristol-Myers Squibb Co.
`
`Abstracts
`
`S317
`
`W7. A Randomized Controlled Crossover Trial of Ketamine in
`Obsessive-compulsive Disorder
`Carolyn I. Rodriguez*, Lawrence S. Kegeles, Amanda Levinson,
`Sue Marcus, Helen Blair. Simpson
`
`Columbia University, Bronx, New York
`
`Background: Obsessive-compulsive disorder (OCD) is a leading
`cause of illness-related disability (1). First-line OCD pharmacolo-
`gical treatments lead to limited symptom relief and typically have a
`lag time of 6-10 weeks before clinically meaningful improvement
`(2). Identifying more effective pharmacological treatments with
`faster onset of action would be a major advance. Medications
`thought
`to modulate the glutamate system are a promising
`new class of pharmacological agents for the treatment of OCD
`(3-8). Ketamine, a non-competitive N-methyl-D-aspartate (NMDA)
`receptor antagonist, modulates glutamate and has been shown to
`have rapid anti-depressant effects in multiple studies (9-15). A
`recent case study of a unmedicated individual with OCD
`without comorbid depression who was given ketamine (0.5 mg/
`kg IV over 40 minutes) showed rapid anti-obsessional effects that
`persisted from 1 to 7 days post-infusion, long after the drug had
`cleared (16). A subsequent open trial of ketamine in ten individuals
`showed modest but significant improvement in OCD symptoms
`over days 1 to 3 following ketamine infusion compared to baseline;
`the majority of individuals with OCD in this study were taking
`multiple medications and had moderate to severe current
`comorbid depression (17). We investigated the effects of ketamine
`on individuals with OCD who were not currently on medications
`and did not have moderate to severe comorbid depression.
`In a randomized, double-blind, placebo-controlled,
`Methods:
`crossover design, unmedicated adults (N¼ 10) with OCD received
`two intravenous infusions: one of saline and one of ketamine
`(0.5 mg/kg) over 40 minutes. These infusions were spaced at least 1
`week apart; the order of each pair of infusions was randomized. To
`be eligible, participants were required to have at least moderate to
`severe OCD (Yale-Brown Obsessive-Compulsive Scale [YBOCS]
`score 416) with no or mild depression (Hamilton Depression
`Rating Scale [HDRS-17]o25), and endorse near-constant intrusive
`obsessions (48 hours per day) (18, 19). To assess rapid changes in
`obsessions, the OCD visual analogue scale (OCD-VAS) was used at
`baseline, at 26, 90, 110, and 230 minutes and daily for 7 days post-
`infusion (16). To assess both obsessive and compulsive symptoms,
`the YBOCS scale, designed to be used to assess OCD symptoms at
`1 week intervals, was used at baseline and 7 days post-infusion.
`To monitor depressive symptoms,
`the HDRS-17 was used at
`baseline and 1 and 3 days post-infusion. Response rate of
`obsessions was defined as a minimum of 35% improvement in
`obsessions (as measured by the OCD-VAS), and response rate for
`OCD symptoms was defined as a minimum of 35% reduction in
`OCD symptoms (as measured by the YBOCS).
`Results: All ten participants completed the study. At baseline,
`participants had moderate to severe OCD symptoms (mean YBOCS
`27.1 + /3.4 SD, range: 22-34). On average, there was a significant
`rapid decrease in obsessions (as measured by OCD-VAS) which
`decayed over time and then reached a plateau. Responder rate
`(n¼ 10) of obsessions (as measured by OCD-VAS) at post-infusion
`time points were as follows: 90% at 3 hours, 80% at 1 day, 60% at 2
`days, 50% at 3 days, and 50% until day 7. Responder rate (n¼ 10)
`for OCD symptoms (as measured by YBOCS) was 50% at day 7.
`Responder rate for OCD symptoms among the subset of patients
`(n¼ 5) who got the ketamine infusion first (and thus the effects of
`ketamine could be evaluated at both day 7 and day 14), was 40% at
`day 14. At baseline, participants had minimal depressive symptoms
`(mean HDRS 4.2 + /5.6, range: 0-16). The average depressive
`symptoms of the 10 patients did decrease somewhat after the
`infusion (4.2 + /5.6 to 1.8 + /1.9, F(2,17) ¼ 3.38,
`ketamine
`p¼ 0.058).
`
`ACNP 51st Annual Conference
`
`Page 4 of 133
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`S318
`
`Abstracts
`
`Conclusions: These data suggest that ketamine can rapidly relieve
`symptoms of OCD, and this effect can persist for at least one week
`in 50% of OCD patients with constant intrusive thoughts. A subset
`of individuals had relief for up to two weeks. Future research is
`needed to better understand the mechanism of ketamine’s rapid
`anti-obsessional effect and persistant reduction in OCD symptoms,
`long after the drug has cleared. These insights will help inform the
`development of new treatment strategies for individuals suffering
`with OCD.
`Keywords: Ketamine; Glutamate, Obsessive-Compulsive Disorder,
`Clinical Trial, Pharmacological Therapy
`Disclosure: C. Rodriguez, Nothing to Disclose; L. Kegeles, Part 4:
`Research contract, Pfizer; Research contract, Amgen; A. Levinson,
`Nothing to Disclose; S. Marcus, Nothing to Disclose; H. Simpson,
`Part 4: research contract
`from Neuropharm; medication for
`research study from Janssen.
`
`W8. Safety and Tolerability of Atomoxetine Hydrochloride in a
`Placebo-controlled Randomized Withdrawal Study in Adults with
`Attention-Deficit/Hyperactivity Disorder
`Himanshu P. Upadhyaya*, Angelo Camporeale,
`J. Antoni Ramos-Quiroga, David Williams, Yoko Tanaka,
`Jeannine Lane, Robert R. Conley, Rodrigo Escobar,
`Paula Trzepacz, Albert J. Allen
`
`Eli Lilly and Company, Indianapolis, Indi