Neuropsychopharmacology (2014) 39, S473–S647 & 2014 American College of Neuropsychopharmacology. All rights reserved 0893-133X/14 www.neuropsychopharmacology.org Wednesday, December 10, 2014 cated higher intake of this dose under low reinforcement schedules by CPP-B6 mice, and intake was predicted under both FR1 and F2 reinforcement schedules by CPP Score. W1. Validation of a Procedurally Simple Murine Model However, there were no group differences in elasticity. of Methamphetamine Addiction Vulnerability/ Immunoblotting revealed higher Homer2 expression, which Resiliency in Mice is consistent with prior results from MA-sensitized B6 mice and mice selectively bred for high MA intake and might Matan Cohen, Hanna Barrett, Nimrita Singh, underpin the addiction vulnerable phenotype of CPP-B6 Melissa Wroten, Gema Olivarria, Lana Bubalo, mice. Tod Kippin, Karen Szumlinski* Conclusions: Together, these results provide predictive and University of California at Santa Barbara, Santa Barbara, construct validity for our B6 place-conditioning model California as a high-throughput tool for studying the biobehavioral mechanisms of MA addiction vulnerability/resilience of to Background: Individual variation exists with respect to the our understanding of the etiology and treatment of MA development and severity of drug addiction and this addiction. individual variability reflects a combination of environ- Keywords: resiliency, addiction, vulnerability, homer. mental and genetic factors. However, the biochemical Disclosure: Nothing to Disclose. correlates of addiction vulnerability/resiliency are severely understudied, particularly to the highly addictive psycho- motor stimulant methamphetamine (MA). Even in pre- W2. Robust, Scalable, and Cost-effective High sumably genetically homogeneous populations of C57BL/6J Throughput Production of iPSC-derived Neural (B6) mice, marked variability exists with respect to the Stem Cells/Early Neural Progenitor Cells and Their capacity of repeated MA (4X2 mg/kg) to elicit place- Differentiation into Glutamatergic Neurons conditioning, an index of MA’s motivational/affective valence. While approximately 50% of B6 mice exhibit a Leonardo D’Aiuto, Yun Zhi, Dhanjit Das, Madeleine conditioned-preference (CPP) for a MA-paired environ- Wilcox, Jon Johnson, Lora McClain, Roberto Di Maio, ment, approximately 12% show conditioned aversion Mark Schurdak, Paolo Piazza, Luigi Viggiano, (CPA), and the remaining mice exhibit ambivalence or no Paul Kinchington, Ayantika Bhattacharjee, conditioned response (Neutral). Vishwajit Nimgaonkar* Methods: We tested the predictive validity of studying University of Pittsburgh School of Medicine, Pittsburgh, inbred B6 mice under simple place-conditioning procedures Pennsylvania as a high-throughput strategy for the study of MA addiction vulnerability/resiliency, by correlating phenotype with MA- Background: Induced pluripotent stem cell (iPSC)-based induced locomotor activity, by assaying CPP-, Neutral- and technologies have revolutionized research into human CPA-B6 mice in a place-conditioning version of the diseases by enabling the generation of specified cells in a extinction/reinstatement paradigm, as well as an oral MA renewable manner from individuals of interest. Human self-administration paradigm (10-40 mg/L). We also tested iPSC-based models also offer an unprecedented opportunity the construct validity of this model by examining for to perform high throughput screens of novel drugs for phenotypic differences in the expression of glutamate- neurological and neurodegenerative diseases. Such screens related proteins within the nucleus accumbens core. require a robust and scalable method to generate large Results: CPP Score was inversely correlated with acute MA- numbers of uniformly distributed, differentiated mature induced locomotor hyperactivity, but positively correlated neuronal cells. Currently, available methods based on with the extent to which mice developed locomotor differentiation of embryoid bodies (EBs) or directed sensitization during MA-conditioning. The MA-conditioned differentiation of adherent culture systems are either response was more resistant to extinction in CPP-B6 mice expensive or are not scalable. vs. CPA counterparts and a 2 mg/kg MA challenge injection Methods: We developed a protocol that enabled high reinstated the conditioned response following extinction throughput generation of neuronal stem cells (NSCs)/early only in CPP-B6 mice. CPP-B6 mice also exhibited greater neural progenitor cells (eNPCs) from iPSCs. These cells MA-directed responding during the first several days of were stored or transferred into 384 well plates and self-administration when 20 mg/L MA served as the differentiated into neurons. At least twenty-four 384-well reinforcer, but did not differ from Neutral or CPA mice plates at a density of 3.5 x103 NSCs/NPCs/well could be regarding MA intake of this dose at any time during study. generated from a confluent 6-well plate of iPSCs in 4 weeks When the dose-response function for MA intake was at a cost of $ 28/plate. examined, CPP-B6 mice consumed higher amounts of the Results: Following culture in neurobasal medium supple- 10 mg/L and 40 mg/L solutions, and their CPP Score mented with B27 and BDNF, NSCs/eNPCs principally predicted the intake of the 10 mg/L dose. A comparison of differentiated into glutamatergic neurons expressing mar- response elasticity in response to 10 mg/L MA under kers characteristic of forebrain layer 3 pyramidal cells. increasing schedules of reinforcement (FR1-FR40), indi- Whole-cell patch-clamp experiments indicated that most ACNP 53rd Annual Meeting Abstracts S474 iPSC-derived neurons express functional ligand-gated measured by the change in PANSS total score and CGI-S, channels. respectively. All doses of brexpiprazole were well tolerated. Conclusions: The procedure detailed here enables robust, Keywords: Schizophrenia, Phase III trial, Brexpiprazole, scalable, and cost-effective generation of neurons in Efficacy and safety. numbers required for high-throughput screening. Disclosure: I (Christoph Correll) have been a consultant Keywords: Induced pluripotent stem cells (iPSCs), Neuronal and/or advisor to or have received honoraria from: stem cells (NSCs), High throughput screening, In vitro Actelion, Alexza; American Academy of Child and Adoles- neuronal differentiation. cent Psychiatry, Bristol-Myers Squibb (BMS), Cephalon, Eli Disclosure: Nothing to Disclose. Lilly, Genentech, Gerson Lehrman Group, IntraCellular Therapies, Lundbeck, Medavante, Medscape, Merck, Jans- sen/J&J, Otsuka, Pfizer, ProPhase, Roche, Sunovion, Take- da, Teva and Vanda. Income sources and equity of $10,000/ W3. Brexpiprazole for the Treatment of Acute year or greater: BMS, Janssen/J&J, Lundbeck, Otsuka, Pfizer, Schizophrenia: A Randomized, Controlled Trial ProPhase. Financial involvement with a company constitut- ing45% of personal income: BMS, Lundbeck, Otsuka, Christoph Correll*, Aleksandar Skuban, James Youakim, Pfizer, ProPhase. Funding received from: BMS, Feinstein John Ouyang, Mary Hobart, Stephanie Pfister, Robert Institute for Medical Research, Janssen/J&J, National McQuade, Margaretta Nyilas, William Carson, Raymond Institute of Mental Health, National Alliance for Research Sanchez in Schizophrenia and Depression and Otsuka. Drs. Skuban, Hofstra North Shore-LIJ School of Medicine/Zucker Youakim, Ouyang, Hobart, Pfister, McQuade, Nyilas, Hillside Hospital, Glen Oaks, New York Carson and Sanchez are employees of Otsuka Pharmaceu- tical Commercialization and Development, Inc. Funding for Background: To evaluate the efficacy, and safety/tolerability this study was provided by Otsuka Pharmaceutical Com- of brexpiprazole in patients with acute schizophrenia. mercialization and Development, Inc. (Princeton, USA) and Methods: This was a phase III, multicenter, randomized, H. Lundbeck A/S (Valby, Denmark). double-blind, placebo-controlled trial (NCT01396421). Pa- tients with acute schizophrenia were randomized to fixed doses of brexpiprazole 4 mg, 2 mg, 0.25 mg, or placebo W4. A Pooled Analysis of 3 Randomized, Placebo- (2:2:1:2) for 6 weeks. The primary efficacy endpoint was Controlled, Phase 3 Studies Evaluating the Efficacy, change in Positive and Negative Syndrome Scale (PANSS) Safety, and Tolerability of Adjunctive Armodafinil in total score from baseline to week 6; key secondary endpoint Bipolar I Depression was the change in Clinical Global Impression-Severity Scale (CGI-S) score at week 6. Efficacy analyses were conducted Mark Frye*, Jess Amchin, Ronghua Yang, Terrence Ketter using mixed model repeated measures (MMRM), including Mayo Clinic, Rochester, Minnesota treatment, visit, site and treatment-by-visit interaction as fixed effects, and baseline score-by-visit as covariate. A gate Background: Depressive episodes associated with bipolar I keeping average effect method was applied to control for disorder may warrant adjunctive pharmacotherapy. Indeed, multiple comparisons (at an alpha level of 0.05) before lurasidone is FDA-approved as adjunct therapy with lithium proceeding with the comparisons for 2 mg and 4 mg or valproate for bipolar I depression. Armodafinil (R- brexpiprazole versus placebo. The 0.25 mg group was modafinil) is a wakefulness-promoting, low-affinity dopa- included to establish a non-effective or minimally effective mine transport inhibitor currently approved in the US for dose range of brexpiprazole. the treatment of excessive sleepiness associated with Results: The gate keeper test of