The goals of the project Social Cognition and Functioning in Schizophrenia (SCAF) were to (1) identify the domains to target from social neuroscience for translation to clinical schizophrenia research, (2) identify the paradigms that represent these domains for which the neural substrates are well documented, (3) adapt these paradigms for use in schizophrenia clinical trials, (4) assess the psychometric properties of these measures, and (5) assess the external validity of these measures. The articles in this theme section present the initial findings from the SCAF project. As more training and psychopharmacological studies evaluate interventions for social cognition, the articles in this theme section are intended to serve as a guide for informed design decisions about possible endpoints in clinical trials

Green, Michael F.

Penn, David L.

PubMed

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1189Schizophrenia Bulletin vol. 39 no. 6 pp. 1189–1191, 2013 doi:10.1093/schbul/sbt128Advance Access publication September 26, 2013© The Author 2013. Published by Oxford University Press on behalf  of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.comGoing From Social Neuroscience to Schizophrenia Clinical TrialsMichael F. Green*,1,2 and David L. Penn3,4 1Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA; 2Department of Veterans Affairs, Desert Pacific Mental Illness Research, Education, and Clinical Center (MIRECC), Los Angeles, CA; 3Department of Psychology, University of North Carolina, Chapel Hill, NC; 4Outreach and Support Intervention Services (OASIS) Program, University of North Carolina, Chapel Hill, NC*To whom correspondence should be addressed; 760 Westwood Plaza, Room 77–361, Semel Institute for Neuroscience and  Human Behavior, University of California, Los Angeles, Los Angeles, CA 90024-1759, US; tel: 310-268-3376, fax: 310-268-4056,  e-mail: mgreen@ucla.eduThe goals of the project Social Cognition and Functioning in Schizophrenia (SCAF) were to (1) identify the domains to target from social neuroscience for translation to clini-cal schizophrenia research, (2) identify the paradigms that represent these domains for which the neural substrates are well documented, (3) adapt these paradigms for use in schizophrenia clinical trials, (4) assess the psychometric properties of these measures, and (5) assess the external validity of these measures. The articles in this theme sec-tion present the initial findings from the SCAF project. As more training and psychopharmacological studies evaluate interventions for social cognition, the articles in this theme section are intended to serve as a guide for informed design decisions about possible endpoints in clinical trials.Key words: social cognition/social neuroscience/ schizophrenia/clinical trialsSocial cognition has emerged as an area of great interest for schizophrenia research. In fact, a search on PubMed with the terms social cognition, schizophrenia, and the year 2012 pulls up 303 articles on this topic. Numerous studies in this area have examined topics such as neural correlates of social cognitive activation tasks, patient-control differences on measures from various social cognitive domains, links to daily functioning, and the commonalities and differences in social cognition across different psychiatric illnesses.Social cognition has also become a treatment target in schizophrenia, as seen in the active development of novel training interventions,1–3 as well as attempts at pharmaco-logical treatments.4–6 Treatment studies require critical deci-sions about endpoints. To demonstrate a treatment effect for social cognition in a clinical trial, What measures should be used to show improvement? Are these measures reliable enough for clinical trials? Can they be repeated without compromising the results? Are they practical for multisite studies? and Are they linked to specific neural systems? For social cognition, these questions are largely unanswered.An ongoing project funded by the National Institute of Mental Health (NIMH) entitled, Social Cognition and Functioning in Schizophrenia (SCAF) is attempting to address these questions. The goals of this project were to (1) identify the domains that are ripe for extensions from social neuroscience to clinical schizophrenia research, (2) iden-tify the paradigms that tap these domains and for which the neural substrates are well documented, (3) adapt these paradigms for use in schizophrenia clinical trials, (4) assess the psychometric properties of these measures, and (5) assess the external validity of these measures (ie, their rela-tionships to functionally meaningful variables). The SCAF project conceptually grows out of the NIMH Initiative, Cognitive Neuroscience for Treatment Research to Improve Cognition in Schizophrenia (CNTRICS).7 CNTRICS held a series of consensus meetings to identify the challenges in adapting measures from cognitive neuroscience and social neuroscience for use in clinical trials of schizophrenia.8 A related project collected data on newly developed para-digms from a subset of the CNTRICS domains, but social cognition and social neuroscience were not represented.9 Hence, the SCAF project was designed to fill a large gap in the literature, starting with the articles in this theme section.The paradigms examined in the SCAF project were considered to be novel for psychosis research—there had not been published studies in schizophrenia at the time the study started (see the following articles for complete descriptions of the domains and paradigms). In addition, they assess social cognitive subprocesses not covered by commonly used measures in psychosis research. The investigators on this project were under no illusions about 1190M. F. Green & D. L. Pennthe difficulty of this translational approach. It is common for measures that work extremely well with college stu-dents in the scanner to crash and burn when applied to chronically ill patients with psychotic disorders. There are many ways for such measures to fail, and among the most common are scaling problems (floor or ceiling effects), poor reliability (test-retest or inter-rater), prob-lems with repeated assessments (eg, tasks that have an ah-ha moment in which an answer is revealed), or feasibility (too long, too hard, or too dull).A related project with an overlapping group of investiga-tors, Social Cognition Psychometric Evaluation (SCOPE),10 is evaluating the suitability of several existing social cogni-tive measures for use in clinical trials. The primary goals of the SCOPE project are to achieve a consensus on the cur-rent social cognitive domains studied in schizophrenia and to evaluate psychometric properties of existing measures to determine their suitability for clinical trials. The measures selected through the SCOPE project will differ from those in SCAF in several ways. First, they assess a particular sub-set of social cognitive domains. Relevant areas of social processing are not covered, such as empathy, self-other processing, nonverbal/nonfacial emotion recognition, and automatic aspects of social processing. Second, the tasks did not come from social neuroscience, such as studies using functional magnetic resonance imaging and electrophysiol-ogy. As a result, their neural substrates are typically unclear. Based on the different selection priorities, the SCOPE and SCAF projects are evaluating nonoverlapping sets of mea-sures. With their emphases on existing measures (SCOPE) and adaptations from social neuroscience (SCAF), these 2 projects are complementary.The 3 articles in this theme are the first batch of pub-lications from the SCAF project. As the project is still ongoing, future articles will capitalize on the larger sam-ple sizes, eg, by using structural equation modeling. The primary psychometric and external validity data, how-ever, are contained in the articles in this theme.The first article presents the conceptual foundation for the SCAF project, and it describes the process used to guide the selection of the domains and paradigms.11 This article places these activities and data in the larger context of intervention trials. It also describes the selec-tion criteria that were used to arrive at a small number of experimental paradigms from social neuroscience, and the current knowledge of the neural substrates of those paradigms.The second article is a detailed psychometric evalu-ation of the paradigms with samples of patients with schizophrenia and healthy controls.12 In this article, we present findings for test-retest reliability, between-group effect sizes, utility as a repeated measure (including prac-tice effects), issues of scale attenuation (floor and ceiling effects), practicality, and tolerability. These data indicate the degree to which the measures are suitable for multisite clinical trials on each of these factors.The third article in this theme examines the external validity of the measures.13 Specifically, we consider how well the measures relate to functional capacity and com-munity outcome. We also examine the measures’ incremen-tal validity—the extent to which they explain variance in functioning beyond that provided by a standard social cog-nitive measure of facial affect identification and beyond nonsocial cognition. These relationships are important to understand because social cognition may be more proxi-mal (in terms of a causal pathway) to daily functioning than are perceptual and nonsocial cognitive processes.14Taken together, the articles in this theme offer 1 model of how to identify and evaluate paradigms from novel research areas for use with clinical psychiatric disorders. The problems we encountered apply equally well to adapt-ing measures from other areas of basic science; social neu-roscience, however, provides a good test case. The articles in this theme provide a summary of the theoretical basis for the paradigms we selected, as well as psychometric and validity data that can be used by clinical trialists when designing clinical trials. As more studies examine social cognition in schizophrenia and other psychotic disorders, and as more studies evaluate training and psychopharma-cological interventions for social cognition, the articles in this theme are intended to serve as a guide for informed decisions about relevant social cognitive domains and potential endpoints for treatment studies.FundingNational Institute of Mental Health (MH087618, MH043292, and MH065707 to M.F.G.).AcknowledgmentsDr Green reports having been a consultant to Abbott laboratories (AbbVie), Biogen, and Roche, he is a mem-ber of the scientific board for Mnemosyne, and he has received research funds from Amgen. Dr Penn reports no financial interests or potential conflicts of interest.References 1. Horan WP, Kern RS, Tripp C, et  al. Efficacy and specific-ity of social cognitive skills training for outpatients with psy-chotic disorders. J Psychiatr Res. 2011;45:1113–1122. 2. Wölwer W, Frommann N, Halfmann S, Piaszek A, Streit M, Gaebel W. Remediation of impairments in facial affect rec-ognition in schizophrenia: efficacy and specificity of a new training program. Schizophr Res. 2005;80:295–303. 3. Roberts DL, Penn DL. Social cognition and interaction train-ing (SCIT) for outpatients with schizophrenia: a preliminary study. Psychiatry Res. 2009;166:141–147. 4. Pedersen CA, Gibson CM, Rau SW, et  al. Intranasal oxy-tocin reduces psychotic symptoms and improves Theory of Mind and social perception in schizophrenia. Schizophr Res. 2011;132:50–53.1191Going From Social Neuroscience  5. Davis MC, Lee J, Horan WP, et  al. Effects of single dose intranasal oxytocin on social cognition in schizophrenia. Schizophr Res. 2013;147:393–397.  6. Fischer-Shofty M, Brüne M, Ebert A, Shefet D, Levkovitz Y, Shamay-Tsoory SG. Improving social perception in schiz-ophrenia: the role of  oxytocin. Schizophr Res. 2013;146: 357–362. 7. Carter CS, Barch DM. Cognitive neuroscience-based approaches to measuring and improving treatment effects on cognition in schizophrenia: the CNTRICS initiative. Schizophr Bull. 2007;33:1131–1137. 8. Ochsner KN. The social-emotional processing stream: five core constructs and their translational potential. Biol Psychiatry. 2008;64:48–61. 9. Gold JM, Barch DM, Carter CS, et  al. Clinical, func-tional, and intertask correlations of measures developed by the Cognitive Neuroscience Test Reliability and Clinical Applications for Schizophrenia Consortium. Schizophr Bull. 2012;38:144–152. 10. Pinkham AE, Penn DL, Green MF, Buck B, Healey K, Harvey PD. The Social Cognition Psychometric Evaluation (SCOPE) study: results of the expert survey and RAND panel. Schizophr Bull. In press. 11. Green MF, Lee J, Ochsner KN. Adapting social neurosci-ence measures for schizophrenia clinical trials, Part 1: fer-rying paradigms across perilous waters. Schizophr Bull. This issue. 12. Kern RS, Penn DL, Lee J, et al. Adapting social neuroscience measures for schizophrenia clinical trials, Part 2: trolling in the depths of psychometric properties. Schizophr Bull. This issue. 13. Olbert CM, Penn DL, Kern RS, et al. Adapting social neu-roscience measures for schizophrenia clinical trials, Part 3: fathoming external validity. Schizophr Bull. This issue.  14. Green MF, Hellemann G, Horan WP, Lee J, Wynn JK. From perception to functional outcome in schizophrenia: mod-eling the role of ability and motivation. Arch Gen Psychiatry 2012;69:1216–1224.

Going From Social Neuroscience to Schizophrenia Clinical Trials

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