Neuropsychopharmacology (2012) 38, S314–S446 & 2012 American College of Neuropsychopharmacology All rights reserved 0893-133X/12 S314 www.neuropsychopharmacology.org Poster Session III Conclusions: In this pooled analysis, adjunctive aripiprazole Wednesday, December 05, 2012 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 W2. Treatment with Adjunctive Aripiprazole Results in range in the mild group. The greater response with adjunctive Significant Improvement Compared with Continued aripiprazole demonstrates the utility of this strategy to manage Antidepressant Monotherapy in Patients with Mild, Moderate, depression in a wide spectrum of patients. and Severe Major Depressive Disorder References 1. Thase ME, et al. Examning the efficacy of adjunctive J Craig. Nelson*, Thomas D. Stewart, Ainslie Hatch, aripiprazole in major depressive disorder: a pooled analysis of 2 Kimberly Largay, Elizabeth E. Bellochio, Sabrina V. Marler, studies. Prim Care Companion J Clin Psychiatry. 2008;10:440-7.2. Ross A. Baker, John Sheehan, Robert M. Berman Berman RM, et al. Aripiprazole augmentation in major depressive disorder: a double-blind, placebo-controlled study in patients with University of California, San Francisco, California inadequate response to antidepressants. CNS Spectr. 2009;14: 197-206.3. Kearns NP, et al. A comparison of depression rating Background: The severity of a patient’s depressive symptoms scales. Brit J Psychiat. 1982;141:45-9. may inform treatment decisions. However, current treatment Keywords: aripiprazole, depression, antidepressants, MADRS, guidelines are based on trial data that group patients of varying treatment degrees of severity together. To better understand the appropriate Disclosure: J. Nelson, Part 1: Honoraria from Eli Lilly Global, patient for adjunctive aripiprazole in major depressive disorder Lundbeck, Otsuka Asia, Schering Plough/Merck (Asia); consultant (MDD), this post-hoc analysis pooled data from 3 similar, 1,2 for Bristol-Myers Squibb, Cenestra Health, Corcept, Covidien, Eli randomized trials, and stratified patients based on published Lilly, Forest, Lundbeck, Medtronics, Merck, Mylan (Dey Pharma), severity cut-offs on the Montgomery A˚ sberg Depression Rating 3 Orexigen, Otsuka, Pfizer, Sunovion, served on advisory boards for Scale (MADRS). Avanir, Bristol-Myers Squibb, Eli Lilly, Labopharm, Mylan (Dey Methods: These trials enrolled patients with an inadequate Pharma), and Otsuka, Part 2: Honoraria from Eli Lilly Global, response to 1-3 trials of antidepressant therapy (ADT). Each study Lundbeck, Otsuka Asia, Schering Plough/Merck (Asia); consultant had an 8-week prospective ADT phase (Phase B), followed by a for Bristol-Myers Squibb, Cenestra Health, Corcept, Covidien, Eli 6-week randomized phase (Phase C) of adjunctive aripiprazole Lilly, Forest, Lundbeck, Medtronics, Merck, Mylan (Dey Pharma), versus continued antidepressant monotherapy + placebo for Orexigen, Otsuka, Pfizer, Sunovion, served on advisory boards for patients with an inadequate response during the prospective phase. Avanir, Bristol-Myers Squibb, Eli Lilly, Labopharm, Mylan (Dey Inadequate response to ADT monotherapy was defined as o50% Pharma), and Otsuka, Part 3: n/a, Part 4: n/a; T. Stewart, Part 1: reduction in the 17-item Hamilton Rating Scale for Depression Speaker for Bristol-Myers Squibb Co., and Otsuka Pharmaceutical (HAM-D-17) total score, HAM-D-17 total score X14, and Clinical Part 1: Global Impressions-Improvement (CGI-I) score X3. For this post- Co., Ltd.; A. Hatch, Employee of Otsuka Pharmaceutical Part 2: hoc analysis, patients were stratified at the beginning of Phase C by Development & Commercialization, Inc., Employee of Otsuka Pharmaceutical Development & Commercialization, Inc.; MADRS total score into 3 groups: mild (MADRS total score p24), Part 1: moderate (MADRS total score ¼ 25-30), and severe (MADRS total K. Largay, Employee of Otsuka Pharmaceutical Develop- Part 2: score X31). During Phase C, aripiprazole was flexibly dosed with a ment & Commercialization, Inc., Employee of Otsuka target of 10 mg/day. Patients were initiated at 5 mg/day (could Pharmaceutical Development & Commercialization, Inc.; E. Bellochio, Part 1: Employee of Bristol-Myers Squibb Co., Part 2: decrease to 2 mg/day for tolerability) and increased to 10 mg/day Part 3: (could decrease to 5 mg/day for tolerability) at the end of Week 1; Employee of Bristol-Myers Squibb Co., Employee of Bristol- Part 1: the maximum dose was 20 mg/day. Change in MADRS total score Myers Squibb Co.; S. Marler, Employee of Bristol-Myers Squibb Co., Part 2: Employee of Bristol-Myers Squibb Co., Part 3: for adjunctive aripiprazole and adjunctive placebo was assessed at Part 1: the end of 6 weeks using last observation carried forward (LOCF). Employee of Bristol-Myers Squibb Co.; R. Baker, Employee Results: Baseline demographics across the three groups appeared of Otsuka Pharmaceutical Development and Commercialization, Part 2: similar. At the beginning of Phase C, in the aripiprazole group, 224 Inc, Employee of Otsuka Pharmaceutical Development and Commercialization, Inc, Part 3: Employee of Otsuka Pharmaceu- (41%), 206 (38%), and 110 (20%) patients were considered mild, Part 1: moderate, or severe, respectively; in the placebo group, it was tical Development and Commercialization, Inc; J. Sheehan, Part 2: 191 (36%), 179 (34%), and 155 (30%) patients, respectively. Employee of Bristol-Myers Squibb Co., Employee of Bristol- Part 3: At the end of 6 weeks, mean changes in MADRS total score Myers Squibb Co., Employee of Bristol-Myers Squibb Co.; R. Berman, Part 1: Employee of Bristol-Myers Squibb Co., Part 2: between aripiprazole and placebo were significantly different in all three severity groups: mild À7.9 aripiprazole vs. À5.4 placebo Employee of Bristol-Myers Squibb Co. (P ¼ 0.0005); moderate À9.5 aripiprazole vs. À6.3 placebo (P ¼ 0.0001); severe À11.9 aripiprazole vs. À7.4 placebo (P ¼ 0.0001). Statistically significantly differences between aripi- W3. Genomic Predictors of Response to Antidepressant prazole and placebo first appeared at Week 1 (mild or severe) or Treatment in Geriatric Depression Using Genome-wide Week 2 (moderate). In all three groups, the endpoint effect size of Expression Analyses: A Pilot Study aripiprazole treatment was moderate (0.334-0.483). Similarly, mean Helen Lavretsky*, Ascia Eskin, Stanley Nelson, Steve Cole percent improvement in MADRS total score between aripiprazole UCLA, Los Angeles, California and placebo were significantly different in all three severity groups: mild -38% aripiprazole vs. -26% placebo (P ¼ 0.0008); moderate - Background: Depression and antidepressant response are asso- 35% aripiprazole vs. -23% placebo (P ¼ 0.0001); severe -35% ciated with leukocyte gene transcriptional alterations. The present aripiprazole vs. ¼ 22% placebo (P ¼ 0.0002). Adjunctive aripipra- pilot study examined immune cell gene expression with anti- zole was well tolerated across the severity groups, with no trends in depressant treatment in geriatric depression. the proportion of patients reporting an adverse event (AE) based Methods: Genome-wide transcriptional profiles were collected on severity; the most common AEs in the aripiprazole-treated from peripheral blood leukocytes sampled at baseline and 16-week groups were akathisia and restlessness. follow-up from 37 older adults with major depression who were ACNP 51st Annual Conference Abstracts S315 randomized to methylphenidate + citalopram; citalopram + place- Methods: Seventy two cocaine-dependent individuals who were bo; or methylphenidate + placebo. Methylphenidate dose ranged not seeking treatment at the time of enrollment in the study were between 10-40 mg per day, and citalopram dose was 20-40 mg per randomly assigned to receive placebo (n ¼ 15), rivastigmine 3 mg day. Genome-wide transcriptional profiling was carried out in the (n ¼ 14), rivastigmine 6 mg (n ¼ 14), huperzine A 0.4 mg (n ¼ 15), peripheral blood mononuclear cell samples obtained at baseline or huperzine A 0.8 mg (n ¼ 14). Urinanalysis was used to confirm and post-intervention. Promoter-based bioinformatics analyses abstinence from cocaine on the day of admission and during the tested the hypothesis that observed transcriptional alterations were next 7 days. The baseline neurocognitive assessment, which structured by transcription factors implicated in dopaminergic, included measures of attention/information processing (as mea- serotonergic, and neuroplastic pathways. sured by the Continuous Performance Task), verbal learning Results: 25 responder and 12 non-responders gene expression episodic memory (as measured by the Hopkins Verbal Learning profiles were analyzedIn the analyses of covariance controlling for Test), and working memory (as measured by the Dual N-Back treatment group, 2 gene transcripts showed systematic up- Task), was conducted immediately after the washout phase and regulation in non-responders at baseline. Up-regulated genes at prior to the administration of study medication (Day 0). The baseline in non-responders compared to non-responders included follow-up assessment was conducted on Day 8 after participants 1) CA1 carbonic anhydrase gene on chromosome 8 involved in had received rivastigmine, huperzine A, or placebo for seven days reversible hydration of CO2 and respiratory function (fold change (Day 2-8). 2.54; P ¼ 0.03); 2) SNCA -alpha-synuclein