Effect of a fully-deceptive -placebo on behavioural and electrophysiological correlates of delusion proneness

Ilya Demchenko, MSc Candidate Integrated Program in Neuroscience, McGill University, Montreal

July 10th, 2020

A thesis submitted to McGill University in partial fulfillment of the requirements of the degree of Master of

© Ilya Demchenko 2020 Table of Contents

TABLE OF CONTENTS ...... II

ABSTRACT ...... IV

RESUME ...... V

ACKNOWLEDGEMENTS ...... VII

CONTRIBUTIONS ...... VIII

LIST OF ABBREVIATIONS ...... X

THEORETICAL BACKGROUND ...... 1

SCHIZOTYPY CONTINUUM MODEL: FROM TAXONIC TO MULTIDIMENSIONAL ...... 2 SOCIAL ROLES AS INTEGRAL CONSTITUENTS OF DELUSIONAL STATES ...... 4 SOCIAL ROLES AS CONSTRUCTS OF SEMANTIC ...... 5 BIOMARKERS OF SEMANTIC PROCESSING: N400 AND LATE POSITIVE POTENTIAL (LPP) ...... 7 ANTIPSYCHOTIC MEDICATIONS AND THE ROLE OF DOPAMINE ...... 11 PLACEBO/NOCEBO PHENOMENON AND COGNITIVE SCIENCE BEHIND EXPECTATION INTERVENTIONS ...... 13

RATIONALE FOR THE STUDY, HYPOTHESES, AND SPECIFIC AIMS ...... 16

EXPERIMENT 1: ANTIPSYCHOTIC-PLACEBO EXPECTATION INTERVENTION ...... 21

OVERVIEW ...... 21 MATERIALS AND METHODS ...... 21 Eligibility criteria ...... 22 Psychometric scales ...... 23 Statistical Analysis ...... 26 RESULTS ...... 26 Demographic and psychometric characteristics ...... 26 Schizotypy and placebo expectations ...... 29 Schizotypy and the antipsychotic-placebo expectation intervention ...... 29 CONCLUSION ...... 34

EXPERIMENT 2: EFFECT OF A FULLY-DECEPTIVE ANTIPSYCHOTIC-PLACEBO ON THE DRIVE TO PLAY SOCIAL ROLES ...... 35

OVERVIEW ...... 35 MATERIALS AND METHODS ...... 35 Participants ...... 35 Experimental Procedure ...... 36 Psychometric scales ...... 37

ii Stimuli presentation ...... 39 Data acquisition and pre-processing ...... 40 Statistical Analysis ...... 42 RESULTS ...... 44 Effect of the antipsychotic-placebo on social role acceptance ...... 44 Demographic and psychometric characteristics ...... 44 Schizotypy and the tendency to play extraordinary social roles ...... 46 Percentages of accepted social roles ...... 50 Reaction Times (RTs) ...... 51 N400 amplitude ...... 53 LPP amplitude ...... 56 Tendency to play extraordinary social roles and antipsychotic-placebo ...... 60 Demographic and psychometric characteristics ...... 60 Percentages of accepted social roles ...... 61 Reaction Times (RTs) ...... 63 N400 amplitude ...... 65 LPP amplitude ...... 69 Schizotypy and antipsychotic-placebo ...... 75 Demographic and psychometric characteristics ...... 75 Percentages of accepted social roles ...... 76 Reaction Times (RTs) ...... 77 N400 amplitude ...... 79 LPP amplitude ...... 84 CONCLUSION ...... 89

GENERAL DISCUSSION ...... 90

SYNTHESIS OF RESULTS AND COMPARISON TO HYPOTHESES ...... 90 LIMITATIONS AND CHALLENGES ...... 101 FUTURE DIRECTIONS ...... 103

FINAL CONCLUSION AND CONTRIBUTION TO ORIGINAL KNOWLEDGE ...... 105

REFERENCES ...... 107

APPENDIX A ...... 131

APPENDIX B ...... 132

APPENDIX C ...... 133

APPENDIX D ...... 137

APPENDIX E ...... 138

iii Abstract

Consistent with the behavioural conflict they generate, personal drives to play extraordinary social roles (ESRs) were previously found to independently predict delusion-like ideation and disorganization traits seen along the schizotypy continuum. This finding spurred a hypothesis that antipsychotic medications, that have been demonstrated to reduce delusional thinking and disorganization in patients, can reduce this drive by blocking dopaminergic transmission modulating motivational and reward seeking circuits of the prefrontal cortex. The aim of this research was to provide psychometric, behavioural, and electrophysiological evidence of the impact of non-specific antipsychotic-placebo (AP-Placebo) expectations on cognitive mechanisms of social role playing as a factor of delusion proneness. On a sample of healthy individuals (N = 52), the current study showed that presenting the information about common adverse effects of antipsychotic medications differentially shapes treatment expectancies contingent upon participants’ schizotypy profile. Consequentially, one hundred volunteers aged between 18 and 30 were invited to the laboratory to complete a social role acceptance task while the electroencephalography recording was acquired. Half of those participants took a fully- deceptive AP-Placebo prior to the experimental session, while the other half did not take any pill. 401 social role names were individually presented to all participants in two sessions, with the instruction to indicate whether or not they would consider playing the social role at any moment in their life. Each treatment group was split into two subsamples based on their characteristics corresponding to two correlates of delusion proneness – tendency to play ESRs and schizotypy. By means of exploring the percentages of accepted ESRs, the reaction times (RTs), the N400 and the late positive potential (LPP), this study reports a nocebo response in participants with high delusion proneness reflected through the decreased drive to play social roles and the use of simplified cognitive strategies, and an ameliorative placebo response in participants with low delusion proneness reflected through the increased drive to play social roles and the use of complex cognitive strategies. This research differentiates schizotypy and the tendency to play ESRs as two related constructs of delusion proneness and highlights the importance of accounting for the disparate placebo/nocebo response in cognitive tasks involving the administration of antipsychotic medications.

iv Résumé

Conformément au conflit comportemental qu'ils génèrent, les pulsions personnelles en œuvre lors de l’acceptation de jouer des rôles sociaux extraordinaires (RSE) se sont révélées prédicteurs des idéations de type délirantes et des traits de désorganisations observés le long du continuum schizotypique. Cette découverte a conduit à l'hypothèse que les médicaments antipsychotiques, dont il a été démontré qu'ils réduisent les pensées de type délirantes et la désorganisation chez les patients schizophrènes, peuvent aussi réduire cette pulsion en bloquant la transmission dopaminergique modulant les circuits de motivation et de recherche de récompense au niveau du cortex préfrontal. Le but de cette recherche était de fournir des preuves psychométriques, comportementales et électrophysiologiques de l'impact des attentes non spécifiques d’un antipsychotique-placebo (AP-Placebo) sur les mécanismes cognitifs en action lors du jeu de rôle social comme facteur de prédisposition aux délires. A travers un échantillon d'individus en bonne santé (N = 52), la présente étude a montré que la présentation des informations sur les effets indésirables courants des antipsychotiques façonne différemment les attentes de traitement en fonction du profil schizotypique des participants. En conséquence, une centaine de volontaires âgés de 18 à 30 ans ont été invités au laboratoire pour effectuer une tâche d'acceptation de rôles sociaux durant laquelle leur activité électroencéphalographique était enregistrée. La moitié de ces participants ont pris un AP-Placebo totalement trompeur avant la session expérimentale, tandis que l'autre moitié n'a pris aucune pilule. 401 noms de rôles sociaux ont été présentés individuellement à tous les participants en deux séances, avec pour instruction d'indiquer s'ils envisageraient ou non de jouer le rôle social à n’importe quel moment de leur vie. Chaque groupe de traitement a été divisé en deux sous-échantillons en fonction de leurs caractéristiques correspondant à deux corrélats de prédisposition au délire - la tendance à jouer des RSE et la schizotypie. En explorant les pourcentages d'RSE acceptés, les temps de réaction (TR), la N400 et le potentiel positif tardif (LPP), cette étude rapporte une réponse nocebo chez les participants avec une prédisposition au délire élevée reflétée par la diminution de la volonté de jouer des rôles sociaux et l'utilisation de stratégies cognitives simplifiées. Les résultats ont aussi montré, une réponse placebo améliorée chez les participants avec une faible prédisposition aux délire reflétée par la volonté accrue de jouer des rôles sociaux et l'utilisation de stratégies cognitives complexes. Cette recherche différencie la schizotypie et la tendance à jouer des RSE en tant que deux constructions apparentées de la prédisposition aux délires et souligne l'importance de tenir compte

v de la réponse disparate placebo/nocebo dans les tâches cognitives impliquant l'administration de médicaments antipsychotiques.

vi Acknowledgements

Over the past two years, I have had the privilege to work alongside bright and talented individuals who have been continuously holding me up throughout this journey. First and foremost, I would like to express my deepest gratitude to my supervisor, Dr. J. Bruno Debruille, for his continuous guidance and unwavering support. Thank you for giving me the opportunity to learn, to improve my skill set and understanding of the research process, for stimulating my thinking, and encouraging my development as a young scholar. I am forever indebted to the intellectual mentorship you have been providing me with throughout this degree. I would like to commend my advisory committee members, Drs. Martin Lepage, Lalit Srivastava, and Ridha Joober, as well as my program mentor, Dr. Tak Pan Wong, for contributing their suggestions and constructive criticism to this research, and for guiding me along throughout my studies.

Special thanks to my lab colleagues, Amanda Tardif, Matthieu Lenne, Sujata Sinha, and Ashley Chau-Morris. I have had such a pleasure working with every single one of you, thank you for supporting me through challenging times and constantly helping me find solutions. I would like to recognize my research assistants, Gabriela Vélez Largo, Quinta Seon, Yi Hong Bao, and Marisa Sturino, for the hard work that have put into the data collection process and the dedication that each of them has demonstrated. This project would not have been possible without your invaluable contributions. To participants who dedicated their time to these studies, I thank you for your patience and genuine interest in this research.

Lastly, I must acknowledge my allies and champions: my parents (Daria and Alexander), grandparents (Olga and Alexei), and close friends. Without your wisdom, inspiration, and moral fortitude, I would not have been able to complete this degree. Thank you for the years of commitment to me, my passions, and my dreams. In every part of this journey, you have always been by my side.

vii Contributions

This project was made possible thanks to the contribution of the following individuals:

Dr. J. Bruno Debruille (supervisor), who developed the theoretical framework for the project, designed the study and acted as a guarantor, recruited all personnel and provided training, oversaw and guided my academic progress, assisted me with the successful completion of this thesis.

Drs. Martin Lepage, Lalit Srivastava, Ridha Joober, and Tak Pan Wong (committee members and academic mentors), who provided their support and mentorship; oversaw the progress of this thesis and my development as a scholar.

Ms. Ola Mohamed Ali (former graduate student), who contributed to the data collection of the antipsychotic-placebo group in Experiment 2, helped develop the theoretical framework for Experiment 2.

Ms. Gifty Asare (former graduate student), who contributed to the analysis of psychometric, behavioural, and electroencephalography data in Experiment 2, helped develop the theoretical framework for Experiment 2.

Mr. Timothy Hadjis (former graduate student), who contributed to the data collection of the antipsychotic-placebo and the no pill groups in Experiment 2.

Ms. Ana L. Fernandez-Cruz (former graduate student), who organized the evaluation of social role names by 42 independent raters, contributed to the data collection of the antipsychotic-placebo group in Experiment 2, helped develop the theoretical framework for Experiment 2.

Mr. Ishan Walpola (former undergraduate student), who built the set of social role names, organized the evaluation of social role names by 42 independent evaluators and helped develop the theoretical framework for Experiment 2.

viii Ms. Julia Segal (former summer research trainee), who helped develop the theoretical framework for Experiment 2.

Mr. Jean Debruille (computer technician), who developed MATLAB scripts and stimuli sequences as part of the experimental protocol for the social role acceptance task in Experiment 2.

Ms. Gabriela Vélez Largo, Ms. Quinta Seon, Ms. Yi Hong Bao, Ms. Marisa Sturino (current and former research assistants), who scheduled participants, assisted with data collection and data pre-processing in Experiment 2.

My personal contributions included: helping develop the theoretical framework for Experiments 1-2; development of the Expectations Assessment Scale (EAS) for Experiment 1; study design, technological implementation, data collection and quality control in Experiment 1; data collection for the antipsychotic-placebo and the no pill groups in Experiment 2; design of pre-processing pipelines for behavioural and electroencephalography data in Experiment 2; pre-processing all behavioural and electroencephalography data using iWave and MATLAB in Experiment 2; quality control and inspection for all event-related potentials; quality control for all psychometric and behavioural data in Experiments 1-2; performing statistical tests for all psychometric, behavioural, and electroencephalography data; visualizing and interpreting all results; and writing this thesis.

This project was funded in part by the Humboldt Research Fellowship, the Natural and Engineering Research Council of Canada, the Fonds de la Recherche du Québec – Nature et technologies, and the University of Paris 8 Vincennes-Saint-Denis.

ix List of Abbreviations

A-ESR Acceptance of Extraordinary Social Roles ANCOVA Analysis of Covariance ANOVA Analysis of Variance AP Antipsychotic AP-Placebo Antipsychotic-Placebo DA Dopamine DSM-III-R Diagnostic and Statistical Manual, third edition, revised E/I balance Excitation/inhibition balance EAS Expectations Assessment Scale ECI Electro-Cap International EEG Electroencephalography ERP Event-related potential ESR Extraordinary Social Role FDR False Discovery Rate HA-ESR High Acceptors of Extraordinary Social Roles ITI Inter-Trial Interval LA-ESR Low Acceptors of Extraordinary Social Roles LPP Late Positive Potential M Mean MC-SDS The Marlowe-Crowne Social Desirability Scale OSR Ordinary Social Role PDI-21 The 21-Item Peters et al. Delusions Inventory PFC Prefrontal Cortex POMP Percent of Maximum Possible RT Reaction Time SD Standard Deviation SE Standard Error of the Mean SNR Signal-to-noise Ratio SOA Stimulus Onset Asynchrony SPD Schizotypal Personality Disorder SPQ Schizotypal Personality Questionnaire SPQ-B Schizotypal Personality Questionnaire-Brief SR Social Role STAI-Y State-Trait Anxiety Inventory, Form Y

x Theoretical background

Introduction and general aims

This work focuses on behavioural and electrophysiological correlates of schizotypy, that is, the continuum of personality characteristics and experiences ranging from mild imaginative states to extreme forms of (Claridge, 1997). Over the past years, there has been a large number of publications on mirror neurons and how we imitate others, often subconsciously (Marshall & Meltzoff, 2014; Simpson, Murray, Paukner, & Ferrari, 2014; Catmur & Heyes, 2019). This research has complemented our understanding of how child and adult behaviours get acquired automatically by witnessing others. One example of such behaviours are actions that get manifested through our intrinsic drives to play various social roles (SRs). Personal drives to play SRs are schemas acquired by the brain through the observation of real or fictional behaviours of others. Some personal drives correspond to extraordinary social roles (ESRs) existing in our culture (e.g., being a famous actor), while others – to ordinary SRs (OSRs) that most of us have to enact to succeed in our lives (e.g., being a diligent worker).

However, cognitive and behavioural schemas associated with ESRs and OSRs often drastically differ from one another. If the drive to play ESRs is too intense, it might conflict with schemas corresponding to OSRs. Such conflict, theoretically, could be responsible for disorganization, such as the one measured on the schizotypy continuum. Consistent with behavioural conflict they generate, personal drives to play ESRs were found to be an independent factor predicting schizotypy measured by the Schizotypal Personality Questionnaire (Fernandez- Cruz et al., 2016). This finding spurred the hypothesis that antipsychotic medications, that have been demonstrated to reduce delusional thinking and disorganization in schizophrenia patients, would reduce the drive to play ESRs, as this drive could be fueled by greater dopamine-mediated reward expectations (Arias-Carrión & Pöppel, 2007; Bromberg-Martin, Matsumoto, & Hikosaka, 2010; Wang et al., 2019). Through the D2 receptor blockade and the associated increase in dopamine (DA) levels in the prefrontal cortex (PFC), (APs) have a potential to normalize semantic processing deficits seen along the schizotypy continuum (Corlett & Fletcher, 2012; Mohr & Ettinger, 2014; Ettinger et al., 2015). This project aimed to replicate the results of Fernandez-Cruz et al. (2016) and to test whether expectancies associated with antipsychotic intake

1 would have an effect on participants’ drive to play SRs and corresponding semantic processing of contextual information. This study is a preliminary step to further separate such expectation effect from the neurochemical effect of atypical antipsychotics risperidone and olanzapine.

Schizotypy continuum model: from taxonic to multidimensional

The concept of schizotypy was introduced in the early twentieth century when clinicians described milder forms of schizophrenia-like symptoms in individuals prior to the onset of their illness and observed such traits in their non-psychotic relatives (Kraepelin, 1919; Kallman, 1938; Bleuler, 1950; Lidz, Cornelison, Terry, & Fleck, 1958; Heston, 1970; Kwapil & Barrantes-Vidal, 2015). The descriptive psychology tradition, conventional diagnostic nosology, prodromal and psychosis-proneness models as well as the personality psychology research all support the idea of a broader continuum of schizophrenia-spectrum psychopathology, stipulating that schizophrenia is not a categorical psychiatric disorder but rather a dimensional entity (Rado, 1953; Meehl, 1962; Claridge & Beech, 1995; Lenzenweger, 2006; Cochrane, Petch, & Pickering, 2012; Nelson, Seal, Pantelis, & Phillips, 2013; Kwapil & Barrantes-Vidal, 2015).

Based upon his observation of schizophrenic-like behavioural impairment, Rado (1953) initially introduced the term ‘schizogene’ and indicated that the liability for schizophrenia was genetically driven and resulted in the impairment varying from mild to fully schizophrenic. Upon interacting with biological potentiators, a single dominant ‘schizogene’ was theoretically responsible for neurodevelopmental defects, described by Meehl (1962, 1989, 1990) as ‘schizoataxia’. Meehl (1962) proposed that schizoataxia was necessary, although not sufficient, for the development of schizotypy, which he viewed as the personality organization conveying the vulnerability for the development of schizophrenia. According to him, schizotypy traits were present in individuals as precursors of clinical schizophrenia that could either remain stable throughout one’s lifetime or decompensate into full-blown schizophrenia upon one’s exposure to sufficient environmental stressors. These theories corroborated the argument stating that schizotypy is taxonic in nature, thereby suggesting that approximately 10% of the general population is schizotypic and that 10% of all schizotypes will develop schizophrenia (i.e., thus accounting for the 1% prevalence of schizophrenia in the general population worldwide) (Global Burden of Disease and Injury Incidence and Prevalence Collaborators, 2017).

2 An alternative view of schizotypy was propounded by Claridge and Beech (1995), who viewed it as a fully dimensional rather than a quasi-dimensional construct. According to them, schizotypy results from a combination of genetic, environmental, and personality variations that are normally distributed in the general population. The fully dimensional model not only recognizes the dimensionality of schizotypy in the clinical and the subclinical ranges but also incorporates the view that schizotypy traits are part of normal individual differences seen in the general population (e.g., creativity). Claridge and Beech (1995) argued that the expression of schizotypy traits only in their extreme forms constitute clinical disorders, such as schizotypal personality disorder (SPD), attenuated psychotic symptoms syndrome, and schizophrenia. As such, these categories are not considered as separate entities from schizotypy but are proposed to be subsumed within the schizotypy continuum. Moreover, the fully dimensional model regards schizophrenia itself as the breakdown process forming a second psychopathological continuum that ranges from SPD to full- blown psychosis. The fully dimensional approach upholds the imperative role of other factors that make schizophrenia pathological and qualitatively different from high schizotypy.

Today, schizotypy is studied as a dynamic multidimensional construct unconstrained by diagnostic boundaries, with evident heterogeneity at the etiological, developmental, phenotypic, and treatment-response levels. Factor analysis-based studies suggest that positive, negative, and disorganized dimensions of schizophrenia have been successfully replicated in non-clinical schizotypy (Bentall, Claridge, & Slade, 1989; Raine et al., 1994; Cicero & Kerns, 2010). The three- factor model of schizotypy proposes three dimensions that correspond to personality traits listed in the DSM-III-R criteria for SPD. The positive dimension, named cognitive-perceptual or delusion-like ideation, is characterized by disruptions in thought content that ranges from odd beliefs to magical thinking and includes unusual perceptual experiences ranging from illusions to hallucinations. The negative dimension, known as interpersonal, describes the diminution in experiences, such as social anhedonia, alogia, avolition, flattened affect, and general disinterest. The disorganized dimension refers to disruptions in the ability to organize one’s thoughts and behaviours that get manifested through odd speech and eccentric actions. The reliable and valid measurement of these dimensions is essential for decompounding the heterogeneity of schizotypy and schizophrenia.

3 ‘Schizotypy offers a useful and a unifying construct for understanding schizophrenia-spectrum psychopathology. Useful in that it has explanatory power for understanding the development, expression, trajectory, risk and resilience, and treatment of schizophrenia-spectrum conditions, as well as for understanding variation in normal behavior, and unifying because it encompasses a broad spectrum of conditions—schizophrenia, related psychotic disorders, spectrum personality disorders, the , and subclinical expressions—under a single conceptual framework.’ (Kwapil & Barrantes-Vidal, 2016, S366)

Social roles as integral constituents of delusional states

One of the principal components of the cognitive-perceptual dimension of schizotypy is delusional states. Delusions are idiosyncratic, inflexible beliefs that are firmly maintained even in light of the contradictory evidence (Jaspers, 1913; Baker, Konova, Daw, & Horga, 2019). While being the most common symptom of psychosis (Andreasen & Flaum, 1911), the cognitive mechanisms underlying these symptoms remain incompletely understood. Delusions have long been proposed to emerge from pathological inference, the process of shaping one’s beliefs through experience (Hemsley & Garety, 1986). This framework postulates that the cognitive system maintains inferences on hidden states based on available sensory evidence. For instance, through the observation of actions and behaviours of others (sensory evidence), one would subliminally infer their intentions (a hidden state). Aberrations in this process would result in the formation of erroneous beliefs that would contradict the available sensory evidence.

In human life, social roles are ubiquitous and serve a crucial function for one’s psychosocial well-being. Bandura (1997) argued that an individual’s self- of how well one can play given social roles act as the primary ‘cognitive mediator’ in determining their psychological health. This might be particularly relevant to individuals with delusional thinking, who hold false beliefs with extraordinary conviction and resistance to the evidence of the contrary. Because every person learns how to play social roles through observation and imitation of others, as well as through inputs from our environment (media, culture, and television), delusions cannot simply arise from internal morbid processes, as proposed by Hamilton (1978), but are rather based on social role playing. For instance, social agent representation is a prominent feature of persecutory delusions, which typically involve the presence of one or multiple human persecutors, and grandiose

4 delusions, which carry special social relationship to famous individuals (Suhail & Cochrane, 2002; Green et al., 2006).

Cognitive strategies of individuals with delusions function in such a way that more attention is directed towards extraordinary events, involving politics, religion, and business, and less attention is given to everyday situations that provide necessary information to adequately play ordinary social roles. Due to the objectively unrealistic nature of extraordinary social roles and the inability to enact most of them in real life, increased drive to play such roles does not give individuals with delusions a self-perception of efficacy, which only further maintains their psychological state (Talley, Kocum, Schlegel, Molix, & Bettencourt, 2012). The conflict created by opposing drives to play ESRs and OSRs is likely to be partly responsible for diminished verbal IQ scores (Brüne, 2003; Inoeu et al., 2006; Noguchi, Hori, & Kunugi, 2008), poor academic performance (Kendler, Ohlsson, Mezuk, Sundquist, & Sundquist, 2016; Dickson, Cullen, Hodgins, MacCabe, & Laurens, 2018), inadequate social skills (Cutting & Murphy, 1990; Picchioni & Murray, 2008; Niznikiewicz, Kubicki, Mulert, & Condray, 2013;), and, in the context of experimental psychology, lower accuracies and slower reaction times (Vinogradov, Poole, Willis- Shore, Ober, & Shenaut, 1998; Suhr & Spitznagel, 2001; Chambon et al., 2008; Cochrane, Petch, & Pickering, 2012).

Social roles as constructs of semantic nature

From a cognitive semantics perspective, social roles are viewed as mental representations (Masolo, Vieu, Bottazzi, & Catenacci, 2004) or ‘instructions to carry out certain kinds of mental constructions’ (Ducrot, 1985). In other words, social roles constitute schemas that enable us to organize our knowledge into parsable categories. Fauconnier (1988) described social roles as ‘concepts within a mental space that can have values within another mental space by means of a counterpart relation’. Given this perspective, social roles construe a dynamic interplay between role schemas and self-schemas, as they integrate our representations of how one is expected to behave in a particular social role with our own personal fit within that social role - our intrinsic representations of being a role-player. Given the range of social dysfunction seen along the schizotypy continuum (Wang et al., 2015; de Wachter, De La Asuncion, Sabbe, & Morrens, 2016; Aghvinian & Sergi, 2018) as well as deficits in empathy (Henry, Bailey, & Rendell, 2008; Thakkar

5 & Park, 2009; Kállai et al., 2019), interpersonal sensitivity (Miller & Lenzenweger, 2012; Cohen, Mohr, Ettinger, Chan, & Park, 2015; Masilo et al., 2019), emotion recognition (Dicket et al., 2011; Lee et al., 2015; Giakoumaki, 2016), and information processing (Kiang & Kutas, 2005; Johnson, Rossel, & Gleeson, 2008; Wang et al., 2013), the importance of studying social role appraisal in the context of underlying semantic etiology becomes apparent.

Perceptions of the self-concept, the collection of beliefs about oneself, are thought to be a driving force dictating whether an individual would decide to play a particular social role or not (Baumeister, 1999; Lee & Harris, 2013). Consistent with the spreading-activation theory of information processing, social roles describe the mode of participation of an entity in an event and can be viewed as the stimuli of semantic nature (Masolo, Vieu, Bottazzi, & Catenacci, 2004). This model posits that knowledge is organized in a series of interconnected networks, with each concept representing a node and the association between concepts - a connection between nodes (Collins & Loftus, 1975). Consequently, the activation of one node triggers an automatic and immediate spread of activations of related concepts that are in close proximity to each other within a network. For a concept to be processed with efficiency, cognitive inhibition of inappropriately activated representations needs to be performed - an effortful process that requires attentional resources (Debruille, 2007). Thus, from a semantic perspective, social roles can be viewed as nodes organized in a network, with the activation of one node leading to the spread of activations to other related social roles, personality traits, life events, and behaviours. Eventually, those activated concepts need to be inhibited, so that an individual is able to adequately process the information associated with the social role and make a decision on whether to play it or not, in accordance with beliefs they hold about themselves.

One of the promising theories attempting to explain the nature of delusional beliefs hypothesizes that impaired perceptual abilities lead to the encoding of unusual ideas, which results in the formation of idiosyncratic semantic memories with affective and self-referential valence (Rossell, Batty, & Hughes, 2010). Studies have shown that schizophrenia patients with delusions have a fundamentally different organizational structure of semantic information than healthy controls: node architecture appears to be idiosyncratically and illogically organized, with some normal relationships between interrelated concepts completely absent or replaced with abnormal

6 associations (Chen, Wilkins, & McKenna, 1994; Moelter et al., 2005; Kiang, Kutas, Light, & Braff, 2008). This corrupt organization of semantic network compromises the process of verifying beliefs against already stored information, which results in the absence of error detection and, consequently, acceptance and maintenance of erroneous beliefs as if they were plausible. In this fashion, individuals with delusions and high schizotypy appear to be more prone to generating implausible beliefs from the information they receive through the observation of behaviours of others, which shapes their personal drives to play social roles accordingly.

Biomarkers of semantic processing: N400 and late positive potential (LPP)

Semantic processing deficits in schizotypy and schizophrenia have been widely studied using the semantic priming technique – a lexical decision test that evaluates the association between mental concepts (Meyer & Schvaneveldt, 1971). This tool builds on the theoretical notion that it is easier to respond with a word stimulus (i.e., semantic target) when it is preceded by a semantically related context (i.e., semantic prime). For example, if asked to respond with the first word that comes to their mind after seeing the prime word ‘black’, healthy individuals tend to respond ‘white’. In contrast, those with schizophrenia or formal though disorder tend to answer with unusual prime-target association due to abnormal spread of activations within their semantic network, which may lead to the activation of distant nodes (Spitzer, 1997; Kuperberg, 2008; Tonelli, 2014). Semantic priming abnormalities have been reported both in schizophrenia (Manschreck et al., 1988; Spitzer et al., 1994; Minzenberg, Ober, & Vinogradov, 2002) and schizotypy (Johnston, Rossell, & Gleeson, 2008; Kiang, 2010) and appear to be a strong candidate endophenotype for the schizotypy continuum.

With the advent of neurophysiological approaches, such as electroencephalography (EEG) and event-related potentials (ERPs), researchers have been trying to identify prospective biomarkers underlying cognitive deficits in schizophrenia and schizotypy, including abnormalities in semantic processing. EEG is a relatively cost-effective non-invasive technique that provides in vivo characterization of neuronal activity with high temporal resolution. ERPs, or evoked potentials, are changes in brain activity time-locked to the onset of a sensory stimulus. ERPs reflect significant voltage fluctuations that arise from the summation of excitatory and inhibitory post- synaptic potentials within pyramidal neurons of the cerebral cortex (Brunia, Hackley, van Boxtel,

7 Kotani, & Ohgami, 2011). ERPs index the discrete information flow between elements of neuronal network and provide precise neurophysiological evidence of normal and abnormal cognitive processes (Brown, Cooper, Talk, & Jamieson, 2017).

Multiple ERP components have been identified, with each thought to reflect a particular stage of cognitive processing dependent on the experimental paradigm employed and the sensory modality of the stimulus. With regard to semantic processing, the most commonly studied ERP is the N400 (‘N’ to signify its negativity, and ‘400’ to reflect its peak time) – a negative potential peaking approximately 400 ms post stimulus onset, with the maximal negativity over centroparietal electrode sites. The N400 was first discovered by Kutas and Hillyard (1980), who observed that sentences with unexpected endings (e.g., ‘He took a sip from the waterfall') elicited larger negativity relative to the sentences with expected endings (e.g., 'He took a sip from the cup’). Later, it was shown that the N400 is part of the normal brain response to meaningful or potentially meaningful stimuli, including visual and auditory words, faces, objects, and sounds (Kutas & Federmeier, 2000, 2011).

The implications of the N400 in semantic processing are supported by the studies that explored the factors affecting its amplitude. Semantic incongruity (i.e., when the word does not align with the context) is the most well-established modulator of the N400 that has been shown to increase its negativity (Kutas & Federmeier, 2011). Other non-semantic factors, such as high stimulus frequency, high repetition rate, and small orthographic neighbourhood size, were found to elicit smaller N400 (Kutas & Federmeier, 2009). In itself, factors that ease the cognitive processing appear to reduce the amplitude of the N400 while factors that increase the processing difficulty boost its amplitude. Although there is no consensus on the functional significance of the N400, several theories have been proposed including hypotheses focused on semantic integration (Kutas & Hillyard, 1980), semantic memory retrieval and binding (Kutas & Federmeier, 2000; Federmeier & Laszlo, 2009), semantic inhibition (Debruille, 2007), and semantic unification (Hagoort & van Berkum, 2007).

8 N400s to visually presented words are typically widely distributed across the scalp but tend to peak at its maximum over centroparietal electrode sites (Kutas & Hillyard, 1982). Moreover, amplitudes tend to be larger over the right than the left hemiscalp, although, depending on the precise orientation of the electrode dipole, the left hemisphere could also act as the neural generator of electrical activity with a maxima over the right hemiscalp electrode sites (Kutas & Federmeier, 2009). Several attempts to localize the source of the N400 have been made, with the data suggesting that the scalp-recorded N400 reflects activity in a widely distributed set of high-level perceptual areas of the cortex involved in multimodal processing and semantic memory storage, including the anterior medial temporal lobe, superior and middle temporal gyrus, the temporoparietal junction, and, less consistently, the dorsolateral frontal cortex (Haan, Streb, Bien, & Rösler, 2000; Halgren et al., 2002; Tse et al., 2007; Khateb, Pegna, Landis, Mouthon, & Annoni, 2010; Hajra et al., 2018). Nevertheless, solving the EEG inverse problem remains particularly challenging to provide estimation for diffuse sources of scalp activity, so converging evidence from other imaging modalities is needed.

Abnormalities in the N400 amplitude as the index of aberrant semantic processing have been widely studied in the context of clinical schizophrenia. Research suggests that in the experimental setting, semantic processing deficits associated with schizophrenia have variable manifestations dependent upon the stimulus onset asynchrony (SOA) of the employed paradigm (i.e., the amount of time between the onset of stimulus 1 and the onset of stimulus 2). Typically, variations in this time interval allow distinguishing automatic semantic processing, which involves short SOA and likely reflects the activity of the left hemisphere, from controlled semantic processing, which involves long SOA and possibly reflects the activity of the high hemisphere and recruitment of the working memory (Tonelli, 2014). In patients with schizophrenia, smaller N400 amplitudes have been reported for paradigms with short SOA (Kostova, Passerieux, Laurent, & Hardy-Baylé, 2003, 2005; Niznikiewicz, Mittal, Nestor, & McCarley, 2010), while larger N400 amplitudes have been observed in paradigms with long SOA (Kiang, Kutas, Light, & Braff, 2008; Kiang, Christensen, Kutas, & Zipursky, 2012). Together, these results provide evidence for hyperactivation of semantic networks in schizophrenia manifested in the simplification of automatic processes at the earlier stage but increased cognitive load for controlled processes at the later stage (for review, see Mohammad & DeLisi, 2013).

9 The hypothesis of hyperactive semantic networks along the schizotypy continuum has been confirmed in some but not all studies. It has been shown that individuals with high SPQ scores display reduced N400 amplitude in relation to semantically unrelated prime-target pairs – a phenomenon termed ‘semantic illusion’ (Kiang & Kutas, 2005; Kiang, Prugh, & Kutas, 2010). Kiang et al. (2010) also reported the association between the cognitive-perceptual cluster of SPQ and smaller N400 direct priming effects (i.e., N400 difference between unrelated and directly related targets) at both short and long SOAs, as well as with smaller N400 indirect priming effects (i.e., N400 difference between unrelated and indirectly related targets) at short SOA. These findings suggest that individuals with high schizotypy establish inappropriate semantic associations more easily in comparison to healthy individuals, which is reflected in the N400 reduction. Other studies reported a differential association of schizotypy dimensions with the N400 amplitude. For instance, Prévost et al. (2010) showed that high schizotypy individuals displayed a bigger N400 in relation to related and unrelated prime-target pairs at long SOA paradigm, with the N400 amplitude showing a significant correlation with the interpersonal and the disorganization clusters of SPQ but not the cognitive-perceptual cluster. These authors suggest that delusion proneness in individuals with high schizotypy may be related to the disorganization dimension where the context of presented information is not properly maintained in the working memory. This hypothesis was corroborated by Morgan, Bedford, and Rossell (2006) who reported abnormalities in semantic processing specifically associated with the disorganized dimension of schizotypy.

Another candidate biomarker of the semantic processing is the late positive potential (LPP), also known as the late posterior complex (LPC) or P600. LPP is a positive ERP component generally beginning around 400-500 ms post-stimulus onset, with a maxima over parietal electrode sites. It was first characterized by the studies that examined the repetition and recognition effects, where a bigger LPP (i.e., more positive) was observed for repeated/recognized items in comparison to newly presented ones (Friedman, 1990; Smith & Guster, 1993; Paller, Kutas, & McIsaac, 1995). Although the exact functional significance of the LPP continues to be debated, it has been suggested that this component indexes conscious evaluation (Juottonen, Revonsuo, & Lang, 1996) and attentional orienting to recollected information (Rugg & Curran, 2007). In other words, LPP indexes ‘the extended retrieval of semantic and episodic information and the integration of that

10 information with the contents of working memory’ (Petten, Kutas, Lkuender, Mitchiner, & McIsaac, 1991). Research studies suggest that the LPP amplitude is bigger when more information is consciously extracted from the stimulus and placed into the working memory (Donchin & Coles, 1988; Vogel, Luck, & Shapiro, 1998; Sergent, Baillet, & Dehaene, 2005), as well as upon the presentation of the stimuli that transfer more than one meaning (e.g., ambiguous faces, word equivocality) (Debruille, Brodeur, & Hess, 2011; Del Goleto, Kostova, & Blachet, 2016). The LPP has thus been traditionally associated with conscious explicit memory processes, in contrast to the N400, which is thought to reflect unconscious implicit processes. Patients with schizophrenia typically show reduced LPP amplitude – a possible neural marker of attentional and working memory dysfunction (for review, see Pritchard, 1986). Several studies also reported the reduced LPP amplitude in participants with high schizotypy (Niznikiewicz et al., 1999; Song, Kim, & Kim, 2011; Del Goleto et al., 2016) but further research is needed to characterize the LPP in this population.

Antipsychotic medications and the role of dopamine

Since the discovery of the antipsychotic action of chlorpromazine in the 1960s, neurochemical theories as a heuristic principle for interpreting the phenomenology of schizophrenia have received widespread attention of the research community. The classical dopamine hypothesis of schizophrenia postulates that the hyperactive dopamine D2 receptor neurotransmission in the mesolimbic pathway contributes to the formation of positive symptoms, while the hypoactive dopamine D1 receptor neurotransmission in the mesocortical pathway is partly responsible for negative and cognitive symptoms (Iversen & Iversen, 2007; Howes & Kapur, 2009). Subtle but similar neurochemical abnormalities have been reported in healthy individuals with high schizotypy, which supports the biological basis underlying the continuum (Woodward et al., 2011; Corlett & Fletcher, 2012; Mohr & Ettinger, 2014).

With regard to semantic processing, dopamine is thought to modulate the balance of glutamatergic and GABAergic synaptic interaction in cortical microcircuits recruited during sustained (Winterer & Weinberger, 2004; Tonelli, 2014). In healthy individuals, semantic processing starts from the separation between relevant (signal) and irrelevant (noise) stimuli. Dopamine is thought to increase the contrast between signal and noise by maintaining the

11 excitation/inhibition (E/I) balance of the network (Copland, McMahon, Silburn, & de Zubicaray 2009). While the post-synaptic activity of D2 receptor is thought to reflect the production of the sense of salience to the environment, the D1 receptor stimulation ensures the network stability and semantic update (Winter & Weinberger, 2004; Corlett, Taylor, Wang, Fletcher, & Krystal, 2010; Tonelli, 2014).

In schizophrenia, frontocortical hypodopaminergia appears to decrease the signal-to-noise ratio (SNR) and disinhibit the network, which leads to the increased experience of noise from irrelevant stimuli (Tonelli, 2014). Consequently, this leads to overactive semantic processing and the recruitment of distant representations. Since the mesocortical dopaminergic pathway indirectly regulates the activity of mesolimbic dopaminergic neurons through the Glutamate-GABA E/I balance (Laruelle, Kegeles, & Abi-Dargham, 2003), destabilized network aggravates the activity of the mesolimbic pathway in schizophrenia patients, which augments their focus on irrelevant stimuli. This manifests through excessive and inadequate attention directed towards ordinary stimuli that are experienced with new, extraordinary, and unusual meaning (Kapur, Mizrahi, & Li, 2005). The role of dopamine in semantic processing is further supported by the administration of levodopa to healthy individuals, where the induced state of hyperdopaminergia was found to diminish the semantic priming effect (Kischka, Kammer, Maier, Weisbrod, & Spitzer, 1996) and modulate patterns of hemispheric dominance (Mohr et al., 2005). Studying these intermediate phenotypes might thus help the scientific community to unravel the complexities of dopamine contribution to cognitive abnormalities seen along the schizotypy continuum.

In light of this evidence, studying the mechanisms of antipsychotic medications in the context of semantic processing and its biomarkers might be of particular relevance. Three studies have shown that treatment with antipsychotic medications attenuates semantic priming deficits in schizophrenia patients, as indexed by normalization of the N400 ERP component (Condray, Steinhauer, Cohen, van Kammen, & Kasparek, 1999; Condray, Siegle, Cohen, van Kammen, & Steinhauer, 2003; Besche-Richard, Iakimova, Hardy-Baylé, & Passerieux, 2014). In these studies, however, the observed effect could have been secondary to the antipsychotic-induced alleviation of positive symptoms, which highlights the importance of reproducing these findings in healthy participants. In the context of schizotypy, only one study by Debruille et al. (2013) hitherto has

12 demonstrated the effect of antipsychotics on the biomarkers of semantic processing. In that study, a small dose of the antipsychotic olanzapine was reported to decrease the amplitude of the anterior N400 in high but not in low schizotypy participants who completed the semantic categorization paradigm. Moreover, olanzapine had no effect on the ERPs elicited by meaningless stimuli in the auditory oddball task, which corroborated the notion that the antipsychotic specifically targeted dopamine-modulated semantic networks. It was suggested that olanzapine could target two semantic processes: the spread of automatic activations and the inhibition of inappropriate representations. According to the theories of embodied cognition, the topology of this effect potentially reflects the modulation of action and emotion-related representations associated with specific words (Borghi & Cimatti, 2010). Such representations are thought to be stored within the PFC networks (Rozzi & Fogassi, 2017).

Placebo/nocebo phenomenon and cognitive science behind expectation interventions

In recent years, there has been a trend towards increasing placebo effects in schizophrenia clinical trials, and, as a consequence, diminishing drug-placebo differences (Kemp et al., 2008). In this context, the importance of isolating the neurochemical effect of antipsychotics from the non-specific effects of the antipsychotic-placebo has become apparent. According to the classical definition of Shapiro and Morris (1978), ‘a placebo is defined as any therapy or component of therapy used for its nonspecific, psychological, or psychophysiological effect, or that is used for its presumed specific effect but is without specific activity for the condition being treated' (p. 371). While placebo response may depend on clinical conditions, therapeutic relationship and the type of treatment, other factors at an individual level are often meaningful, including certain biomarkers, personality traits, emotional and motivational constructs, as well as the characteristics of the healing ritual (Weimer, Colloca, & Enck, 2015; Webster, Weinman, & Rubin, 2016; Kern, Kramm, Witt, & Barth, 2020).

Regarding the psychological mechanisms underlying the placebo response, the notable attention of researchers has been directed towards the response expectancy theory. This approach is based on the premise that a placebo produces an effect because the recipient expects it to (Kirsch, 1985; Steward-Williams & Podd, 2004; Peiris, Blasini, Wright, & Colloca, 2018). Kirsch (1985) defined response expectancies as anticipations for the occurrence of nonvolitional responses, such

13 as nausea, pain, sexual arousal, and emotional reactions. At least some of the effects of expectancies on certain variables are unmediated, meaning that expectation of subjective experience leads directly to subjective experience without any intermediate mechanism (Kirsch, 1997). Inherently, one’s expectancies are shaped by previous experiences by means of instructional or observational learning.

Creating treatment outcome expectations has become an accepted part of the research and clinical practice. As a general rule, the effect of expectations on one’s physiological or psychological state can be either positive or negative (Eknoyan, Hurley, & Taber, 2013). Placebo response is induced by expectations of a positive treatment outcome, while a nocebo response is induced by expectations of a negative treatment outcome. The specific role of expectations in placebo/nocebo response has been substantiated by numerous research studies (for review, see Meissner, Kohls, & Colloca, 2011). In itself, the expectancy theory posits that the placebo/nocebo response is the product of cognitive engagement and conscious monitoring of a positive/negative outcome (Alphs, Benedetti, Wolfgang Fleischhacker, & Kane, 2012). By selectively paying attention to the signs of change, one takes them as evidence that the treatment has worked. This creates a self-reinforcing positive feedback loop that potentiates the final outcome.

These perspectives suggest that expectancies can be manipulated in the experimental setting with intervention techniques. The most commonly applied expectation intervention approaches are verbal suggestion, conditioning, and mental imagery (Peerdeman et al., 2016). Of particular interest are imagery interventions – techniques involving the active generation of cognitive representations of an outcome through implicit suggestions (Gryll & Katahn, 1978; Holmes, Arntz, Smucker, 2007). While traditionally viewed within the scope of quasi-visual phenomena, invoked representations can in fact involve multiple sensory modalities, with several studies corroborating auditory, proprioceptive, kinesthetic, haptic, and olfactory imagery (for review, see Nanay, 2018).

Cognitive science portrays mental imagery as embedded within and contingent upon a language-like mental representational system, mentalese, from which it extracts its semantic content (Pylyshyn, 1973; Kosslyn, Thompson, & Ganis, 2006; Thomas, 2019). Grounded in early theories of behaviourists, cognitive psychologists today believe that imagery appeals to the

14 retrieval and storage of mental representations, which are viewed as being embodied and individuated by their functional and computational role in cognitive processes. As such, expectations that one has about the effects of medication can be viewed as semantic concepts facilitating or interfering with the activation of other related semantic representations, since such concepts might or might not be organized within the same semantic network (Shapiro, 1968; Schneider, 2007). Paying selective attention to the signs of change would facilitate the recruitment of the corresponding semantic representations, which would potentiate the final placebo response. In contrast, not paying attention to the signs of change but instead to the non-specific effects would interfere with the activation of the corresponding semantic representations. Instead, the representations corresponding to non-specific expectancies would be recruited, ultimately leading to the nocebo response if such expectancies have negative valence. In the context of social role acceptance, the placebo effect would manifest itself in the increased drive to play social roles and the use of more complex cognitive strategies: Participants would accept a greater number of presented SRs and with slower reaction time (RT). The nocebo effect would explain the decrease in the drive to play social roles and the use of more simplified cognitive strategies: Participants would accept a smaller number of presented SRs and would be more impulsive, or faster, at providing their responses.

The cognitive mechanisms of placebo/nocebo response in schizophrenia or schizotypy have not been studied in specific trials. The heterogeneous presentation of schizophrenia with positive, negative, and cognitive symptoms markedly challenges the proper assessment of the placebo response, as some patients might view their psychotic symptoms as rewarding (Murray & Stoessl, 2013). Patient’s expectations and attitudes towards antipsychotics can also vary considerably (Awad, 1993). However, there is evidence that mental imagery is compromised in schizophrenia patients both on the behavioural and the electrophysiological levels (Aleman, de Haan, Kahn, 2005; Sack, van de Ven, Etschenberg, Schatz, & Linden, 2005; Mazhari, Tabrizi, & Nejad, 2015). In conformity with the information processing abnormalities seen along the schizotypy continuum, this spurs a theoretical hypothesis that certain cognitive constituents of the placebo response might be incapacitated in this population.

15 Rationale for the study, hypotheses, and specific aims

The chosen method here and in Fernandez-Cruz et al. (2016) was based on the idea that the drive to play extraordinary social roles (ESRs) could be a factor of disorganization that is independent of other factors contributing to schizotypy and schizophrenia spectrum disorders, such as genetic vulnerability and influence of early environment. As such, the sample was taken from the general population rather than clinical practice. This was done for two reasons. First, schizotypy and schizophrenia patients are relatively rare in the general population, with a prevalence of 3.7% and 1% worldwide, respectively (Rössler et al., 2015; Perälä et al., 2007). Second, recruiting healthy participants eliminates the confounds of suboptimal cognitive functioning. As cognitive deficits of a variable degree tend to be present along the continuum ranging from normality to schizophrenia via schizotypy, such functioning could be associated with difficulty comprehending the full meaning of social roles, which would have biased our results. With that strategy, Fernandez-Cruz et al. (2016) were successful at demonstrating that the propensity to accept ESRs predicts participants’ schizotypal traits, as quantified by the Schizotypal Personality Questionnaire (SPQ) (Raine, 1991). The first specific aim of this project was thus to replicate that finding on a novel sample of healthy participants using an equivalent experimental paradigm. It was hypothesized that participants with a higher percentage of accepted ESRs, again, would have a higher total SPQ score, as well as higher scores for each of three SPQ clusters: (i.e., delusion-like ideation, interpersonal communication, and disorganization) and the scores for the 21-Item Peters et al. Delusions Inventory (PDI-21) specifically designed to operationalize delusional thinking.

Because the tendency to accept ESRs was found to be an independent predictor of schizotypy, the large-scale goal of the current study was to explore whether atypical antipsychotics were able to reduce this tendency if administered at a single minimal dose. Antipsychotic medications have been demonstrated in multiple studies to reduce delusional ideation and restore some aspects of cognitive functioning in schizophrenia patients (Patel, Cherian, Gohil, & Atkinson, 2014; Guilera, Pino, Gómez-Benito, & Rojo, 2009). Specifically, ‘atypical’ antipsychotics were developed in response to observed extrapyramidal symptoms caused by the long-term administration of ‘typical’ antipsychotics, which were also largely ineffective against

16 negative and cognitive symptoms of the disorder. Considering that previous pre-clinical studies were able to establish the efficacy of a single dose of atypical antipsychotics on measures of cognitive performance (Weickert et al., 2003; Hill, Bishop, Palumbo, & Sweeney, 2010; Sumiyoshi, Higuchi, & Uehara, 2013), this paradigm can be adapted into a one-day test that would determine the best antipsychotic medication for a patient. However, because a great proportion of medication effect is typically accounted by expectations and pre-existing notions that patients hold towards an administered medication (Barksy, Saintfort, Rogers, & Borus, 2002; Bingel et al., 2011; Vase & Wartolowska, 2019), it becomes necessary to first isolate the neurochemical effect of the drug from any non-specific effects, such as expectation effects. For this reason, to establish whether expectation effects could influence the propensity to play social roles, the group receiving fully-deceptive inactive treatment has to be compared to a control group that would receive no pill and, thus, would hold no expectations about the effect of a drug. This was the second specific aim of this project, with non-specific expectations theorized to impede semantic processing of social roles in consonance with the spreading-activation theory of information processing.

Given these perspectives, it is known that patients with schizotypy and schizophrenia typically have pre-conceived notions about antipsychotic medications, which might influence their adherence to treatment and therapeutic outcome (Mizrahi, Badby, Zipursky, & Kapur, 2005; Kaar, Gobjila, Butler, Henderson, & Howes, 2019). Usually, such expectations are attributed to the adverse effects of the medication but can also involve non-specific adopted negative beliefs coming from the general misunderstandings of pharmacological treatments, engendered anxiety and suspicion, concerns about influences of medication on their ability to think and perform everyday tasks, as well as expectations shaped by the popular culture surrounding antipsychotics. However, such expectations can also be 'shaped' in the experimental setting, as demonstrated by Wei et al. (2018), for example. These authors reported that expectation interventions, such as verbal suggestion, conditioning procedure, and mental imagery, were able to modulate the degree of placebo and nocebo effects in pain perception. Supported by this idea, the third specific aim of this project was to investigate how expectations differed along the schizotypy continuum and how those expectations mediated the placebo effect on the drive to play social roles.

17 In our study, the presentation of the consent form describing the adverse effects of an antipsychotic could be treated as an expectation intervention. Such intervention would ‘shape’ participants’ expectations before the start of the experiment: Participants would be less concerned about their pre-existing notions surrounding the drug effect and would instead be monitoring the occurrence of any side effects that had been mentioned in the consent form. This would induce a state of hypervigilance and increased attention – a so-called somatic focus that would help such participants better concentrate on the task (Cioffi, 1991; Brown, 2004; Geers, Helfer, Weiland, & Kosbab, 2006). Somatic focus is a relatively common phenomenon stemming from the cognitive- emotional model of the placebo response proposed by Lundh (1987), who argued that selective attention to physical signs of change reinforce the placebo response through cognitive mechanisms of congruency evaluation, as one takes body signals as evidence that placebo works. In addition, the consent form contained a statement mentioning that antipsychotics facilitate the mechanisms allowing us to understand unexpected information, which helps individuals with inaccurate beliefs change their minds. This positive suggestion is what was primarily thought to potentiate the placebo response.

Consistent with the evidence-based association between schizotypy and information processing deficits (Kiang & Kutas, 2005; Johnson, Rossel, & Gleeson, 2008; Wang et al., 2013), the expectation intervention was theorized to work only in individuals who score low on the SPQ while individuals with high schizotypy were expected to retain their pre-existing concerns after reading the consent form. From that standpoint, it was hypothesized that individuals with low delusion proneness would commence the social roles task while in a state of anticipation of a positive treatment outcome and while not concerned about non-specific effects of the drug on their cognitive abilities and performance – hence, there should have been no interference with semantic processing of presented social roles. Because such participants would pay more attention to presented stimuli, more semantic content would be extracted and thereupon placed in the working memory. As such, we would expect to see a general increase in the drive to play social roles and a higher computational load required for semantic processing. In contrast, individuals with high delusion proneness would perform the task while being concerned about non-specific drug effects on their cognition and performance. Such non-specific expectations were hypothesized to interfere

18 with the semantic processing of social roles, which would manifest itself in the decreased drive to accept social roles and the use of simplified cognitive strategies.

Electroencephalography (EEG) and event-related potentials (ERPs) were chosen as the method for the proposed experiment because of their exceptional temporal resolution and the ability to display changes in the electrical activity of pyramidal neurons within milliseconds. ERPs are characterized by distinct components that, based on their polarity, amplitude, latency, and scalp distribution, can provide insight into cognitive processes that occur at precise time points upon social role presentation. Of particular interest is the N400 – a negative potential peaking approximately 400 ms after stimulus presentation, which is thought to index semantic processing (Kutas & Hillyard, 1980). Consistent with theories of embodied cognition, the meaning of the social role can be grounded in internal bodily states, such as perception, action, and emotion (Borghi & Cimatti, 2010). Social roles are hypothesized to trigger a representation of all actions and emotions related to that specific social role, and as such, one would predict that our negative emotions and expectations could interfere with our semantic processing and, hence, would decrease the N400. One example of this is the study by Chwilla, Virgillito, & Vissers (2011), who were successful at showing that the N400 effect was significantly reduced in participants that watched a sad movie compared to those who watched a happy movie. Nevertheless, despite the fact that many studies have shown that expectations play a central role in placebo and nocebo effects (Beneditti, Mayberg, Wager, Stohler, & Zubieta, 2005; Jarcho, Mayer, & London, 2009; Eknoyan, Hurley, & Taber, 2013; Brown & Peciña, 2019), literature concerning the EEG/ERP evidence of these effects in the context of medication intake remains scarce.

While the N400 elicited by purely linguistic concepts has a maximum peak at central and parietal sites, the N400 for action-related concepts seems to be distributed across the frontal sites (Schendan & Ganis, 2012; Debruille, Rodier, Prévost, Lionnet, & Molavi, 2013; Amoruso et al., 2013). We hypothesized that an antipsychotic-placebo would reduce the centroparietal N400 due to interference of placebo expectations with semantic processing, which would index a smaller amount of inhibition of distant representations. This would reflect the impediment with information processing of purely linguistic attributes of social roles and their core meaning. Additionally, we hypothesized that the effect of the antipsychotic-placebo on frontal N400 would

19 be mediated by participant’s delusion proneness. Social roles were theorized to activate a representation of all actions related to that specific role, with frontal N400s reflecting self- referential judgements (i.e., a personal fit within a social role) (Polich, 1985; Watson, Dritschel, Obonsawin, & Jentzsch, 2007) and the subsequent inhibition of representations for actions not aligning with the personal fit with the social role (Debruille et al., 2013; Shang & Debruille, 2013). In those with high delusion proneness, we expected to see a reduction in the frontal N400 due to the influence of negative expectations on the inhibition of distant action-related representations. In those with low delusion processing, we expected to see an increase in the frontal N400 as a result of induced state of somatic focus, which would bolster the computational load of the network and conduce a more efficient inhibition of distant representations.

Given the self-referential judgement and engagement with decision evaluative processes characteristic of the social role acceptance task, we also expected to see a modulation of the LPP amplitude. Consistent with the proposition that the LPP indexes the amount of information consciously extracted from the stimulus and placed into the working memory (Donchin & Coles, 1988; Vogel, Luck, & Shapiro, 1998; Sergent, Baillet, & Dehaene, 2005), we hypothesized that following the smaller amount of inhibition of distant representations, more information would be placed into the working memory accompanied by a larger LPP amplitude. This effect was expected to be smaller in participants with high delusion proneness, as a consequence of simplified processing, and larger in participants with low delusion proneness, as the index of sustained attention and higher computational load. Thus, the fourth specific aim of this project was to investigate the role of antipsychotic-placebo in semantic processing of social roles using the EEG/ERP technique to obtain an objective measurable change in electrical cortical activity signaling the presence of the expectation effect.

20 Experiment 1: Antipsychotic-placebo expectation intervention

Overview

To correctly interpret the effect of an antipsychotic-placebo (AP-Placebo) on behavioural and event-related potential (ERP) measures in the social role acceptance tasks, we developed an online survey aimed at assessing non-specific expectations and attitudes that participants have towards antipsychotic medications. Such expectations can have a profound impact on participants' performance in cognitive tasks reflected through changes in the accuracies and the reaction times (Colaguiri & Boakes, 2010; Colaguiri, Livesey, & Harris, 2011), as well as in amplitudes of certain ERP components (Wager, Matre, & Casey, 2006; Sovilj et al., 2013). Moreover, administering the form with the information about the medication side effects could possibly ‘reshape’ participants’ expectations immediately prior to their participation in the psychology experiment. This would be a form of the mental imagery intervention technique involving implicit suggestions and active generation of multi-sensory cognitive representations of one’s state under the influence of antipsychotics (Holmes, Arntz, & Smucker, 2007; Peerdeman et al., 2016). Given the deficits in information processing (Kiang & Kutas, 2005; Johnson, Rossel, & Gleeson, 2008; Wang et al., 2013) as well as the evidence of self-referential hypermentalization seen along the schizotypy continuum (van der Ven & Merckelbach, 2003; Janik McErlean & Banissy, 2016; Wastler & Lenzenweger, 2019), Experiment 1 explored the extent to which schizotypy moderates the ‘reshaping’ effect of the AP-Placebo expectation intervention.

Materials and Methods

Placebo expectations online survey

Data for the placebo expectations survey was acquired with the use of an open-source survey service LimeSurvey. LimeSurvey services stored the data on a local server of the Social & Cognitive Neuroscience laboratory hosted in Montreal, Canada, in a separate private database with a separate username and password. The survey started with an advertisement that was used for the recruitment of the AP-Placebo group in Experiment 2 (see Appendix A). This advertisement asked whether participants would be willing to participate in the follow-up experiment where they would take a single minimal dose (2.5 mg) of the antipsychotic olanzapine. Participants who answered

21 ‘No’ were unable to proceed further with the survey completion. The purpose of this screening strategy was to recruit participants identical in their demographic and clinical characteristics to the experimental AP-Placebo group that would be completing the social role acceptance tasks (Experiment 2). The survey was composed of a set of demographics questions and three psychometric scales. Participants’ psychometric characteristics were measured with the Schizotypal Personality Questionnaire-Brief (SPQ-B) (Raine & Benishay, 1995) and the State- Trait Anxiety Inventory Form Y (STAI-Y State) (Spielberger, 1983), while placebo expectations were assessed using the adapted version of the Expectations Assessment Scale (EAS) (Boot, Simons, Stothart, & Stutts, 2013; Rabipour & Davidson, 2015; Rabipour, Davidson, & Kristjansson, 2018).

We also thought that participants’ expectations about antipsychotics in the experimental setting could differ from those in the real-life setting, with a possibility that the informed consent form could have ‘reshaped’ participants’ expectations by exposing them to validated information about the antipsychotic and its associated side effects. To account for this possibility, we presented a paragraph from the original consent form of the social roles task describing the common adverse effects of the antipsychotic medication olanzapine (see Appendix B). We administered the EAS questions twice - before and after participants had a chance to familiarize themselves with the paragraph. In the ‘Before’ condition, participants had to provide responses on the basis of their existing knowledge about antipsychotics. In the ‘After’ condition, their responses were ‘reshaped’ by the information presented in the consent form paragraph. This allowed us to examine the extent to which participants’ expectations were influenced by presented information, as well as whether a person’s schizotypy profile moderated such ‘reshaping’ effect

Eligibility criteria

In order to be eligible for the study, participants had to be between 18 and 30 years of age and had to be native English or French speakers with at least ten years of education in either language. All participants had to be right-handed or mostly right-handed, with normal or corrected-to-normal vision, and with no history of seizures, loss of consciousness for more than 5 minutes, migraines lasting for several days, or medical condition that compromises brain function. Other exclusion criteria were personal history of DSM-IV Axis I psychiatric disorders (except for depressive

22 episode that resolved at least two years ago), family or , alcohol or substance abuse, or current use of any medication related to a psychiatric disorder. For the alcohol abuse criterion, participants were excluded if they had, on average, more than 9 drinks per week. For the substance abuse criterion, participants were excluded if they consumed psychotropic substances more than 3 times per week. All subjects gave informed consent prior to accessing the survey and had to certify that they were not under the influence of alcohol, cannabis or cannabis products, or any other psychotropic substance during the survey completion.

Psychometric scales

Schizotypal Personality Questionnaire-Brief (SPQ-B). The Schizotypal Personality Questionnaire-Brief (SPQ-B) was developed as a short version of the original 74-Item Schizotypal Personality Questionnaire (SPQ) to screen for predisposition to DSM-IV defined Schizotypal Personality Disorder (SPD) in a large population (Raine & Benishay, 1995). The instrument consists of the most reliable 22 items from the original SPQ and preserves the assessment of the three clusters of schizotypy (delusion-like ideation, interpersonal, disorganization). Each item where a positive ‘Yes’ response is provided receives a score of 1. The Total SPQ-B score ranges from 0 to 22 and is calculated by summing all positive responses. The criterion validity, as indicated by significant correlation with independent clinical ratings of SPD, is good for the Total SPQ-B (r = .66), the SPQ-B Delusion-like ideation (r = .73), and the SPQ-B Interpersonal (r = .63) scores but is lower for the SPQ Disorganization (r = .36) score. The SPQ-B is recommended for dimensional research on the correlates of schizotypy in the normal population and has been widely used in numerous studies (Fonseca-Pedrero et al., 2007; Mason, 2015; Siddi, Petretto, & Preti, 2016; Kirchner, Roeh, Nolden, & Hasan, 2018; Wong & Raine, 2018). The Total SPQ-B score was used to divide participants into high and low schizotypy subgroups with the median split procedure.

State-Trait Anxiety Inventory, Form Y (STAI-Y State). Anxiety was assessed using the state version of the State-Trait Anxiety Inventory, Form Y – a 40-item Likert scale psychological inventory widely used in the research setting (Spielberger, 1983). The state version includes the following 20 items rated on a 0-4 scale: 1) I feel calm; 2) I feel secure; 3) I am tense; 4) I feel strained; 5) I feel at ease; 6) I feel upset; 7) I am presently worrying about possible misfortunes;

23 8) I feel satisfied; 9) I feel frightened; 10) I feel comfortable; 11) I feel self-confident; 12) I feel nervous; 13) I feel jittery; 14) I am indecisive; 15) I am relaxed; 16) I feel content; 17) I am worried; 18) I feel confused; 19) I feel steady, and 20) I feel pleasant. Scoring should be reversed for anxiety-absent items (10 out of 20 items). The overall state anxiety score is obtained by adding the scores for each item, with a higher score indicating greater anxiety (Spielberger, Gorsuch, Lushene, Vagg. & Jacobs, 1983). Scores are ranging from 20 to 80, with a score of 20-37 indicating no or low anxiety; 38-44 indicating moderate anxiety; 45-80 indicating high anxiety (Julian, 2011). This scale was used to control for potential differences between high and low SPQ-B groups in baseline anxiety before the survey completion.

Expectations Assessment Scale (EAS). To assess participants’ expectations about antipsychotics in relation to specific domains of functioning (e.g., mood, cognitive functions, multi-tasking ability), we administered a set of questions adapted from the Expectations Assessment Scale (EAS) that has been previously used in the context of measuring the perceived effectiveness of treatment-of-interest (Boot, Simons, Stothart, & Stutts, 2013; Rabipour & Davidson, 2015; Rabipour, Davidson, & Kristjansson, 2018). As suggested by the authors, the structure of the EAS can be customized based on the desired outcome measure (Rabipour et al., 2018). Our EAS is comprised of four subscales aiming at assessing different types of expectations: effect presence, effect valence, effect direction, and effect strength (see Appendix C). Each subscale uses a single question that assesses multiple items. As we were interested in what expectations participants had in relation to each of the individual items, we did not compute the total score for any of the four subscales.

Effect presence subscale. The effect presence subscale evaluates perceived expectations of whether an antipsychotic would influence certain domains of functioning or not. The exact wording of the question is as follows: ‘Do you think an antipsychotic medication would affect your [X] to a large extent or not at all?’. This question is administered in relation to the following 19 items: 1) Cognitive functions (attention, memory, visual perception, information processing, and reasoning); 2) Memory; 3) Concentration; 4) Distractibility; 5) Reasoning ability; 6) Multitasking ability; 7) Performance in everyday tasks (e.g., driving, remembering important dates, managing finances, etc.); 8) Thought process; 9) Levels of energy; 10) Anxiety; 11)

24 Impulsivity; 12) Spontaneity; 13) Creativity; 14) Perception of pain; 15) Feeling of nausea; 16) Sleepiness; 17) Movement and motion; 18) Appetite; 19) Sexual function. Each item is rated on a scale of 0-5: 0 – Not at all (no changes in brain activity or noticeable behaviour); 1 – To a small extent (possible changes in specific brain activity, yet unnoticeable in daily life); 2 – To some extent (possible changes in general brain activity, yet unnoticeable in daily life); 3 – To a moderate extent (possible changes in specific brain activity and behaviour); 4 – To a great extent (possible changes in general brain activity as well as noticeable behavioural changes); 5 – To a very great extent (changes in general brain activity as well as noticeable changes in overall thought and behaviour that impact daily life).

Effect valence subscale. The effect valence subscale aims to assess perceived expectations of whether an antipsychotic would affect certain domains of functioning in a positive or a negative way. The question ‘Do you think an antipsychotic medication would affect your [X] very positively or very negatively’ is administered in relation to the following 10 items: 1) Cognitive functions (attention, memory, visual perception, information processing, and reasoning); 2) Memory; 3) Concentration; 4) Distractibility; 5) Reasoning ability; 6) Multitasking ability; 7) Performance in everyday tasks (e.g., driving, remembering important dates, managing finances, etc.); 8) Thought process; 9) Appetite; 10) Sexual function. Respondents rate each time on a 7- point Likert scale. The answers ‘very negatively’, ‘fairly negatively’ and ‘somewhat negatively’ receive a negative score from -3 to -1, the answer ‘I have absolutely no expectations’ receives the score of 0, and the answers ‘somewhat positively’, ‘fairly positively’, and ‘very positively’ receive the positive score from 1 to 3 corresponding to a respective answer.

Effect direction subscale. The effect direction subscale uses adjectives describing feelings and states of mind that are derived from the domains of functioning assessed in the effect presence subscale. The question ‘A single minimal dose of an antipsychotic would make me [X]’ asks respondents to indicate whether an antipsychotic medication would amplify or dampen certain physical and psychological states. The subscale includes the following 9 items: 1) Tired; 2) Anxious; 3) Impulsive; 4) Spontaneous; 5) Creative; 6) Able to feel pain; 7) Nauseous; 8) Sleepy; 9) Agitated. Respondents rate each time on a 7-point Likert scale. The answers ‘significantly less’, ‘much less’ and ‘somewhat less’ receive a negative score from -3 to -1, the answer ‘I have

25 absolutely no expectations’ receives the score of 0, and the answers ‘somewhat more’, ‘much more’, and ‘significantly more’ receive the positive score from 1 to 3 corresponding to a respective answer.

Effect strength subscale. The effect strength subscale also uses adjectives but instead evaluates perceived expectations of the extent to which an antipsychotic would make someone feel a certain way. The question 'Indicate to what extent you think an antipsychotic would make you feel [X]' is asked in relation to the following 8 items: 1) Sad; 2) Joyful; 3) Emotionally blunted; 4) Excited; 5) Weird; 6) Defenceless; 7) Confused; 8) Psychotic (having difficulties determining what is real and what is not, having false beliefs, seeing or hearing things that others do not see or hear). Each item is rated on a 0-5 scale: 0 – Not at all; 1 – To a small extent; 2 – To some extent; 3 – To a moderate extent; 4 – To a great extent; 5 – To a very great extent.

Statistical Analysis

All participants who completed the survey were split into high and low schizotypy subgroups using the median split procedure for their Total SPQ-B scores. Demographic and psychometric characteristics of high and low schizotypy participants were compared with the independent- samples t-test, with Levene’s test (1960) used to correct for the heterogeneity of variance. Distributions of both schizotypy subsamples on each item of the EAS were compared non- parametrically in the ‘Before’ and ‘After’ conditions with the Mann-Whitney U test. Wilcoxon signed-rank test was run to assess the change in EAS scores between the ‘Before’ and ‘After’ conditions, that is, after the presentation of the informed consent form. The false discovery rate (FDR) method was used to adjust for multiple comparisons (Benjamini & Hochberg, 1995).

Results

Demographic and psychometric characteristics

Of the 410 respondents who provided the informed consent and accessed the content of the survey, N = 174 were willing to participate in the real setting follow-up study that would involve the administration of an antipsychotic (Figure 1). All those subjects completed the screening

26 Did not provide Accessed the survey informed N = 484 consent N = 74

Provided informed consent

N = 410

‘No’ Would you be interested in participating in a follow-up N = 236 study involving the administration of a low dose (2.5 mg) of an Did not meet the eligibility antipsychotic (risperidone criteria or olanzapine)? N = 90 • Personal history of a DSM-IV Axis I psychiatric disorder (N = 22) • Family history of schizophrenia / bipolar ‘Yes’ disorder / manic depression (N = 5) • Personal history of a DSM-IV Axis I N = 174 psychiatric disorder + family history of schizophrenia / bipolar disorder (N = 7) • Other (N = 56) Enrollment N = 84

Did not finish the Did not confirm their Included in the survey online identity analysis N = 10 N = 22 N = 52

High Low schizotypy schizotypy N = 25 N = 27

Figure 1. Diagram of participants enrolled in the antipsychotic-placebo expectation intervention study.

27 Table 1 Demographic and psychometric characteristics of participants included in the analysis of the antipsychotic-placebo expectation intervention effect High schizotypy Low schizotypy (N = 25) (N = 27) Sex: male, % (N) 36.0 % (9) 40.7 % (11) Age, M (SD) 23.44 (3.93) 23.77 (4.36) Years of Education, M (SD) 16.25 (2.33) 16.28 (2.51) Total SPQ-B, M (SD) 9.12 (3.24) **** 2.15 (1.59) SPQ-B Delusion-like ideation, M (SD) 3.08 (1.78) **** 0.52 (0.85) SPQ-B Interpersonal, M (SD) 4.52 (2.02) **** 0.93 (1.11) SPQ-B Disorganization, M (SD) 1.52 (1.58) * 0.70 (0.99) STAI-Y state, M (SD) 39.84 (10.44) 35.85 (8.56) Note. SPQ-B, Schizotypal Personality Questionnaire-Brief; STAI-Y state, The State-Trait Anxiety Inventory (Form Y). * p < .05, ****p < .0001

questionnaire and N = 84 met the eligibility criteria for the study. Of these 84 subjects, 10 did not finish the survey in its entirety and 22 were unable to confirm their identity through follow-up communication. Due to the online nature of the study, such respondents were excluded from the analysis. The remaining N = 52 subjects fully completed the survey and were split into high (N = 25) and low (N = 27) schizotypy subgroups according to the median split of their Total SPQ-B scores.

High and low schizotypy subgroups did not significantly differ in terms of sex, age, and level of education (Table 1). Those with high schizotypy had moderate levels of anxiety before the survey completion, while those with low schizotypy presented themselves with no to low levels of anxiety. Nevertheless, no significant differences were observed for the STAI-Y scores between the two subgroups. As expected, subjects with high schizotypy had a significantly higher Total SPQ-B score (t(34.25) = -9.72, p < .00001, r2 = .73) as well as the scores for all three SPQ clusters: delusion-like ideation (t(33.82) = 6.55, p < .00001, r2 = .56), interpersonal (t(36.55) = 7.86, p < .00001, r2 = .63), and disorganization (t(50) = 2.24, p = .03, r2 = .09).

28 Schizotypy and placebo expectations

Our analysis of expectations that participants held before reading the consent form did not reveal any significant differences between those with high versus those with low schizotypy, for none of the four EAS subscales. Schizotypy profile did not appear to moderate those expectations that are based on prior beliefs about antipsychotic medications. After both subgroups read the description of the adverse effects in the consent form, however, high SPQ-B scorers expected that an antipsychotic would affect certain domains of functioning to a greater extent than what low SPQ-B scorers expected (Table 2). Significant differences between the two groups were seen for the following effect presence items: multitasking ability (U = 177.00, p = .001, FDR-p = .04, η2 = .18, one-tailed), performance in everyday tasks (U = 183.00, p = .002, FDR-p = .04, η2 = .17, one- tailed), reasoning ability (U = 196.50, p = .004, FDR-p = .04, η2 = .14, one-tailed), concentration (U = 202.50, p = .005, FDR-p = .04, η2 = .13, one-tailed), impulsivity (U = 199.00, p = .004, FDR- p = .04, η2 = .14, one tailed), and spontaneity (U = 206.00, p = .006, FDR-p = .04, η2 = .12, one- tailed). No differences were found for the effect valence, the effect direction, or the effect strength items.

Schizotypy and the antipsychotic-placebo expectation intervention

The effect of the expectation intervention is summarized in Table 3a for low schizotypy participants and in Table 3b for high schizotypy participants. In brief, the information in the consent form had a bigger effect on those with low schizotypy and small to no effect on those with high schizotypy. Relative to those expectations the participants held before reading the consent form, low schizotypy subjects expected that an antipsychotic would have a smaller effect on their concentration (Z = -3.46, p = .00006, FDR-p = .0008, η2 = .44, one-tailed), creativity (Z = -3.71, p = .00002, FDR-p = .0005, η2 = .51, one-tailed), distractibility (Z = -3.76, p = .00003, FDR-p = .0005, η2 = .50, one-tailed), energy (Z = -2.94, p = .001, FDR-p = .01, η2 = .32, one-tailed), memory (Z = -2.55, p = .004, FDR-p = .03, η2 = .24, one-tailed), multitasking ability (Z = -3.57, p = .00004, FDR-p = .0004, η2 = .47, one-tailed), performance in everyday tasks (Z = -2.58, p = .004, FDR-p = .03, η2 = .25, one-tailed), sexual function (Z = -2.32, p = .01, FDR-p < .05, η2 = .20, one-tailed), and thought process (Z = -3.17, p = .0003, FDR-p = .003, η2 = .37, one-tailed) after they read the consent form. In contrast, after adjusting for multiple comparisons, high schizotypy participants

29 Table 2 High (N = 25) and low schizotypy (N = 27) between-group comparison (Mann-Whitney U test) on the EAS items after the consent form paragraph presentation EAS question EAS Item Median response Median response p η2 type for High SPQ-B for Low SPQ-B (1-tails) (N = 25) (N = 27) Effect Presencea Memory To some extent To a small extent .04 .06 Concentration To some extent To a small extent .005 .13 Distractibility To some extent To a small extent .01 .10 Reasoning Ability To a moderate extent To a small extent .004 .14 Multitasking Ability To some extent To a small extent .001 .18 Performance in To some extent To a small extent .002 .17 everyday tasks

Thought Process To some extent To a small extent .02 .09 Impulsivity To some extent No expectations .004 .14 Spontaneity To some extent No expectations .006 .12 Creativity To a small extent No expectations .02 .08 Feeling of Nausea To some extent To a small extent .04 .06 Movement To some extent To a small extent .01 .10 Effect Valenceb Sexual Function No expectations Somewhat negatively .01 .10 Effect Directionc Joyful To a small extent No expectations < .05 .06 Note. EAS, Expectations Assessment Scale; SPQ-B, Schizotypal Personality Questionnaire-Brief. a Effect Presence Question type: Do you think an antipsychotic would have an effect on X or not? b Effect Valence Question type: Do you think an antipsychotic would affect X very negatively or very positively? c Effect Direction Question type: To what extent do you think an antipsychotic would make you feel X? Bold denotes statistical significance after the Benjamini-Hochberg (1995) adjustment for multiple comparisons α = .05

did not display such difference for any of the abovementioned domains. However, both the high and the low schizotypy subgroups thought that an antipsychotic would have a smaller effect on anxiety (High schizotypy, Z = -2.79, p = .002, FDR-p = .01, η2 = .31, one-tailed; Low schizotypy, Z = -3.82, p = .00001, FDR-p = .0005, η2 = .54, one-tailed), impulsivity (High schizotypy, Z = - 3.08, p = .0006, FDR-p = .007, η2 = .38, one-tailed; Low schizotypy, Z = -3.75, p = .00002, FDR- p = .0005, η2 = .52, one tailed), and spontaneity (High schizotypy, Z = -2.99, p = .001, FDR-p = .01, η2 = .36, one-tailed; Low schizotypy, Z = -3.86, p < .00001, FDR-p = .0005, η2 = .55, one-

30 tailed) after they read the consent form, with that effect being more profound among low schizotypy participants for all three domains.

Initially, low schizotypy participants thought that an antipsychotic would affect their memory somewhat negatively while high schizotypy participants had no expectations. After all participants read the consent form, both high and low schizotypy subjects held no expectation pertaining to the valence of the effect of an antipsychotic on their memory, with a statistically significant difference between the two conditions observed for those with low schizotypy only (Z = -2.41, p = .009, FDR- p = .04, η2 = .22, one-tailed). Additionally, those with low schizotypy initially anticipated that an antipsychotic would make them somewhat more tired, while those with high schizotypy had no expectations. After the informed consent form was presented to all participants, the scores for that item shifted towards the median in the low schizotypy subgroup. In contrast, the high schizotypy subgroup displayed significantly higher scores indicating that they expected an antipsychotic to make them somewhat more tired (Z = -2.56, p = .007, FDR-p = .04, η2 = .26, one-tailed).

We also saw the effect of the consent form on the anticipation that an antipsychotic would make one feel emotionally blunted and weird. Both the high and the low schizotypy participants expected that an antipsychotic would make them emotionally blunted to a lesser extent after they read the consent form (High schizotypy, Z = -2.68, p = .003, FDR-p = .02, η2 = .29, one-tailed; Low schizotypy, Z = -2.44, p = .006, FDR-p = .03, η2 = .22, one-tailed). Additionally, the low schizotypy subgroup thought that an antipsychotic would make them feel weird to a small extent in both conditions, but with the scores shifting towards the median after those subjects read the consent form (Z = -2.44, p = .008, FDR-p = .04, η2 = .22, one-tailed). In contrast, high schizotypy subjects initially thought that an antipsychotic would make them feel weird to some extent but to a small extent after the expectation intervention, with no significant difference observed after the FDR adjustment.

31 Table 3a Within-group comparison (Wilcoxon signed-rank test) on the EAS items before and after the consent form paragraph presentation for participants with low schizotypy (N = 27) EAS Question type EAS Item Before reading the After reading the p η2 consent form consent form (1-tailed) paragraph paragraph Effect Presencea Anxiety To a moderate extent To a small extent .00001 .54 Concentration To some extent To a small extent .00006 .44 Creativity To some extent Not at all .00002 .51 Distractibility To some extent To a small extent .00003 .50 Energy To a moderate extent To some extent .001 .32 Impulsivity To a moderate extent Not at all .00002 .52 Memory To some extent To a small extent .004 .24 Multitasking ability To some extent To a small extent .00004 .47 Performance in To some extent To a small extent .004 .25 everyday tasks

Sexual function To some extent To a small extent .01 .20 Spontaneity To some extent Not at all < .00001 .55 Thought process To some extent To a small extent .0003 .37 Effect Valenceb Memory Somewhat negatively No expectations .009 .22 Effect Directionc Tired Somewhat more Somewhat more .02 .17 Effect Strengthd Emotionally Blunted To some extent To a small extent .006 .22 Weird To a small extent To a small extent .008 .22 Note. EAS, Expectations Assessment Scale; a Effect Presence Question type: Do you think an antipsychotic would affect your [X] to a large extent or not at all? b Effect Valence Question type: Do you think an antipsychotic would affect your [X] very positively or very negatively? c Effect Direction Question type: Do you think an antipsychotic would make you feel more or less [X]? d Effect Strength Question type: Indicate to what extent you think an antipsychotic would make you feel [X] Table presents only the EAS items where significant differences were observed after the Benjamini-Hochberg (1995) adjustment for multiple comparisons, α = .05

32 Table 3b Within-group comparison (Wilcoxon signed-rank test) on the EAS items before and after the consent form paragraph presentation for participants with high schizotypy (N = 25) EAS Question type EAS Item Before reading the After reading the p η2 consent form consent form (1-tailed) paragraph paragraph Effect Presencea Anxiety To a great extent To some extent .002 .31 Concentration To a moderate extent To some extent .07 .09 Creativity To some extent To a small extent .02 .18 Distractibility To a moderate extent To some extent .09 .07 Energy To a moderate extent To some extent .04 .12 Impulsivity To a great extent To some extent .0006 .38 Memory To some extent To some extent .20 .03 Multitasking ability To some extent To some extent .43 .002 Performance in To some extent To some extent .43 .002 everyday tasks

Sexual function To some extent To a small extent .04 .14 Spontaneity To a moderate extent To some extent .001 .36 Thought process To a moderate extent To some extent .08 .08 Effect Valenceb Memory No expectations No expectations .49 .0003 Effect Directionc Tired No expectations Somewhat more .007 .26 Effect Strengthd Emotionally Blunted To a moderate extent To a small extent .003 .29 Weird To some extent To a small extent .02 .17 Note. EAS, Expectations Assessment Scale; a Effect Presence Question type: Do you think an antipsychotic would affect your [X] to a large extent or not at all? b Effect Valence Question type: Do you think an antipsychotic would affect your [X] very positively or very negatively? c Effect Direction Question type: Do you think an antipsychotic would make you feel more or less [X]? d Effect Strength Question type: Indicate to what extent you think an antipsychotic would make you feel [X] Table presents only the EAS items where significant differences were observed after the Benjamini-Hochberg (1995) adjustment for multiple comparisons, α = .05

33 Conclusion

The results of this online study suggest that showing the informed consent form with the information about the medication side effects exemplifies a form of the mental imagery expectation intervention. Participants’ expectations about the effect of the antipsychotic on specific domains of functioning were modified after the presentation of the paragraph extracted from the original consent form used for the social role acceptance tasks (Experiment 2). Schizotypal traits appear to moderate the effect of this intervention as significant differences were seen primarily in those with low but not high schizotypy. As such, in low schizotypy participants, the expectation intervention was highly effective at reducing non-specific placebo expectations for cognitive, executive, and affective domains of functioning. This subgroup would thus commence impending cognitive tasks with minimal concerns about the medication influences on their performance and mental abilities. In contrast, the expectation intervention failed to ‘reshape’ non- specific expectations for the majority of cognitive and executive domains of functioning in those with high schizotypy. This observation is consistent with the well-grounded evidence of information processing deficits and self-referential hypermentalization that is seen along the schizotypy continuum. High schizotypy subjects would thus start the cognitive tasks with retained non-specific adopted negative concerns about influences of medication on their cognitive abilities and executive functions, which could have a profound impact on their semantic processing.

34 Experiment 2: Effect of a fully-deceptive antipsychotic-placebo on the drive to play social roles

Overview

The fundamental goal of the current experiment was to investigate the effect of expectations associated with the intake of a fully-deceptive antipsychotic-placebo (AP-Placebo) on the correlate of delusion proneness –the drive to play extraordinary social roles (ESRs). The social role acceptance task is a novel task with high ecological validity specifically designed to investigate the decision-making processes for choices encountered in everyday life. The approach we have taken was first to establish the general effect of AP-Placebo expectations on behavioural and electrophysiological measures. Subsequently, we explored the mediation effect of schizotypy and the correlate of schizotypy – the tendency to play ESRs (Fernandez-Cruz et al., 2016). As demonstrated by Fernandez-Cruz et al., high schizotypy is associated with a greater percentage of accepted ESRs and slower reaction times (RTs). In that study, however, participants with a high tendency to play ESRs showed faster RTs for accepted SRs and slower RTs for rejected SRs than participants with a low tendency to play ESRs. This suggests that the tendency to play ESRs is a phenotype that is somewhat distinct from schizotypy, although highly related to it. As such, the relationship between these two phenotypes will be further explored in the context of the AP- Placebo response.

Materials and Methods

Participants

One hundred right-handed healthy participants (45 M, 55 F) aged between 18 and 30 years old (M = 22.89 y.o., SD = 3.00 y.o.) were recruited through English or French online advertisements. The antipsychotic-placebo (AP-Placebo) and the no pill groups were recruited in separate cohorts, with the advertisement for the AP-Placebo group explicitly stating that upon their arrival to the lab participants would take a single minimal dose of an antipsychotic (risperidone or olanzapine). Participants were either English or French native speakers or had completed at least ten years of education in either language (M = 14.98 years, SD = 1.66 years). All subjects had a normal or corrected-to-normal vision and reported no previous history of neurological conditions, medical conditions that compromise brain functioning, or history of head injury with loss of

35 consciousness for longer than 5 minutes. Additionally, participants were excluded from the study if they reported any personal history of DSM-IV Axis I psychiatric disorder (except for depressive episode that resolved at least two years ago), family history of schizophrenia or bipolar disorder, alcohol or drug abuse, or current use of any medication related to a psychiatric disorder. All participants completed a demographics questionnaire where they provided information regarding their sex, age, and level of education. Pre-experimental and post-experimental fatigue levels were also assessed.

Experimental Procedure

Participants were invited to the lab for one testing session. Upon arrival, subjects were informed about the purpose of the study and signed the informed consent form approved by the Douglas Ethics Review Board (project number: IUSMD-06-42). For the AP-Placebo group, the informed consent explicitly stated that participants would receive either 2.5 mg of olanzapine or 1 mg of risperidone and contained the description of the associated side effects for each medication. No verbal information about the medication was given to the participants. Subsequently, participants completed a set of questionnaires in their preferred language (English or French), and the electrode cap was placed (Figure 2).

Subjects were seated comfortably in a dimly lit room, 70-100 cm from the computer screen. After the general explanation of the task instructions and a short practice run session, the AP- Placebo group received an orally disintegrating capsule that looked identical to olanzapine or risperidone tablets but that contained saccharose (placebo). The emptiness of the mouth was checked after swallowing. The no pill group did not receive any tablet. Immediately after, the EEG recording session began during which participants provided responses in the sequence of presented social roles (session 1). Right after, a one-hour lunch break was given to all participants, superseded by the second session of the task (session 2). This time window was chosen because the neurochemical effect of olanzapine and risperidone at this dose is known to occur one hour post-administration, according to the peak plasma concentration (Heykants et al., 1994; Callaghan, Bergstrom, Ptak, & Beasley, 1999). The stimuli sequences for session 1 and session 2 were counterbalanced across subjects. After the EEG recording, participants completed post-experiment

36 Demographics and pre-experimental questionnaires

SESSION 1 SOCIAL ROLE ACCEPTANCE TASK Participants thought that an antipsychotic has NOT yet taken its effect

1 hour break

SESSION 2 SOCIAL ROLE ACCEPTANCE TASK Participants thought that an antipsychotic has taken its effect

Debriefing and post-experimental questionnaires

Figure 2. Experimental design of the study. questionnaires and had a debriefing session at which they provided feedback about the experiment. This experimental protocol achieved the specific aim of comparing the placebo group to a control group that had no expectations about the drug effect.

Psychometric scales

Schizotypal Personality Questionnaire (SPQ). The Schizotypal Personality Questionnaire (SPQ) is a self-report scale modeled on the DSM-III-R criteria for the schizotypal personality disorder (SPD) (American Psychiatric Association, 1987; Raine, 1991; Dumas et al., 2000). The instrument was designed to measure SPD traits in the general population and has been widely used

37 as a psychometric tool in the research of schizotypy correlates (Tarbox & Pogue-Geile, 2011; Mason, 2015; Fonseca-Pedrero et al., 2018). SPQ is comprised of 74 Items assessing personality traits on 9 subscales, with each subscale contributing to one of the three SPQ clusters (delusion- like ideation, interpersonal, disorganization). Each item where a positive 'Yes' response is provided receives a score of 1. The Delusion-like ideation cluster is derived by summing together all positive items corresponding to the 'Ideas of Reference', 'Odd Beliefs and Magical Thinking', and 'Unusual Perceptual Experience' subscales. The Interpersonal cluster includes the items assessing 'Excessive Social Anxiety', 'No Close Friends', 'Constricted Affect', and 'Suspiciousness'. Lastly, the Disorganization cluster consists of the added ‘Odd Speech’ and ‘Odd and Eccentric Behaviour’ subscales. The Total SPQ score ranges from 0 to 74 and is obtained by computing the sum of all positive responses. The scale has high internal consistency (Cronbach’s α = 0.90-0.91) and a good two-month test-reliability (Intraclass correlation coefficient, ICC = 0.82) (Raine, 1991; Dumas et al., 2000; Koo & Li, 2016). In the current study, the Total SPQ score was used to divide participants into high and low schizotypy subgroups with the median split procedure. Administering this questionnaire addressed the specific aim of replicating the results of Fernandez- Cruz et al. (2016) and assessing how expectations of the drug effect differ along the schizotypy continuum.

The 21-Item Peters et al. Delusions Inventory (PDI-21). The 21-Item Peters et al. Delusions Inventory (PDI-21) measures delusional ideas on 21 ‘Yes/No’ Items, with an accompanying 5- point Likert scale reflecting associated distress, preoccupation, and conviction for each Item (Peters, Joseph, Day, & Garety, 2004). The instrument has adequate internal consistency (Cronbach’s α = 0.82) and significant Spearman’s correlations between the initial and subsequent PDI-21 scores confirming its test-retest reliability. Each item where a positive ‘Yes’ response is provided receives a score of 1. The Total PDI-21 ‘Yes’ score ranges from 0 to 21 and is calculated by summing all positive responses. PDI-21 Distress, PDI-21 Preoccupation, and PDI-21 Conviction scores reflect the sum of the scores for each respective PDI-21 cluster and range from 0 to 105. This questionnaire was administered to refine our measurement of the content of delusional belief in the general population.

38 The Marlowe-Crowne Social Desirability Scale (MC-SDS). Social desirability bias refers to the tendency of respondents to answer questions and perform behavioural tasks in a manner that makes them more desirable to other people (Salkind, 2010; Krumpal, 2011). This attempt to 'look good to others' can compromise the validity of experimental research, especially if participants are aware that they are being studied. Due to the nature of the social role acceptance task, some individuals might conceal their internal disapproval of social roles, which would result in the inflated percentage of accepted SRs. Additionally, social desirability bias has a significant impact on responses to questions about psychiatric problems (Zemore, 2012). To control for this tendency of participants to self-represent in a favourable manner, we thus administered the Marlow-Crowne (1960) Social Desirability Scale (MC-SDS) – a 33-Item False/True instrument structured in such a way that the individuals with a strong incentive to self-display as socially acceptable would give responses that are unlikely to be observed in the general population. MC-SDS scores are ranging from 0 to 33, with a score of 0-8 denoting low scorers; 9-19 denoting average scorers; 20-33 denoting high scorers.

Stimuli presentation

Before the experiment, 401 social roles (SR) names were rated on a 9-point Likert scale by 42 independent raters who were given the definition of four criteria (ordinary, extraordinary, favourable, unfavourable) (see Appendix D). ‘Extraordinariness’ referred to a degree at which a social role would exceed human physical or mental capabilities, while ‘favourability’ – to a degree at which a social role would benefit an individual in an advantageous manner. SR names were presented to evaluators in random order and were split into four categories according to median ratings: ordinary favourable (e.g., mother, piano teacher, jogger), ordinary unfavourable (e.g., vandal, homeless person, drunk driver), extraordinary favourable (e.g., Hercules, Harry Potter, astronaut), extraordinary unfavourable (e.g., bandit, vampire, slave). We ensured that there were no significant differences across these four categories in the mean number of letters and the mean frequency of social role use (computed from Google books Ngram viewer figures).

39

doctor 1800 ms

BLINK! 1000 ms

+ 300-1000 ms

bandit 1800 ms

Figure 3. Social role task sequences used in the experiment.

The set of SRs was split into two sequences of 200 and 201 stimuli, with each sequence being balanced for the proportion of four categories. Roles were presented one at a time, for 1800 ms, in black writing on a white background at the centre of a computer screen (Figure 3). Each role was immediately followed by a ‘BLINK!’ stimulus which lasted for 1000 ms. The trial ended with a fixation cross of a duration randomized between 300 ms and 1000 ms. Thus, the ITI of our paradigm was between 3100 ms and 3800 ms. E-Prime (Schneider, Eschman, & Zuccolotto, 2012) and a MATLAB plug-in Psychotoolbox-3 (Brainard, 1997; Pelli, 1997; Kleiner et al., 2007) were used for implementation. Participants were asked to decide as quickly and as accurately as possible whether or not they would consider themselves playing a presented social role at any moment in their life. Participants had to provide answers by pressing a ‘Yes’ or ‘No’ button with the index or middle finger. Only responses given between 300 ms and 2500 ms after the onset of an SR were included in the analysis to eliminate trials that participants did not pay enough attention to, were too hesitant, or provided spontaneous responses to. The design of these sequences allowed us to obtain quantifiable behavioural measures of accuracies and reaction times (RTs), which addressed the specific aims of replicating the results of Fernandez-Cruz et al. (2016) and further exploring how expectations mediate placebo/nocebo effect on the drive to play social roles.

Data acquisition and pre-processing

Electroencephalography (EEG) was recorded from 28 tin electrodes on the Electro-Cap International (ECI) cap with the Neuroscan and iWave acquisition software. Response accuracies and reaction times (RTs) were subsequently extracted from the recording file. The 28 electrodes were placed according to the modified 10-20 system (American Electroencephalographic Society,

40 1991). Linked ears (A1/A2) were used as the reference and the ground was placed 2 cm anterior to Fz. Electrodes were grouped into three subsets: sagittal (Fz, Fcz, Cz, Pz), parasagittal (Fp1/2, F3/4, Fc3/4, C3/4, Cp3/4, P3/4, O1/2), and lateral (F7/8, Ft7/8, T3/4, Tp7/8, T5/6) (see Appendix E). The impedance was measured before the experiment using a 30Hz current and was kept below 5 KΩ. The high- and low-pass filters had their half amplitude cut-off set at 0.01Hz and 100 Hz, respectively. A 60 Hz electronic notch filter was also used. EEG signals were digitized at a 248 Hz sampling rate and stored in a single data file along with the stimulus and response codes.

The data were processed using MATLAB R2018a and the MATLAB plug-in EEGlab v.14.1.2b (Delorme & Makeig, 2004). Trials with no responses or responses with RTs shorter than 300 ms or longer than 2500 ms were rejected. For the EEG data, baseline correction was set by computing the mean voltage in the -200 ms to 0 ms time window (pre-stimulus onset) and then subtracting this mean from every single point in the -1000 ms to 1200 ms EEG epoch. Artifact rejection eliminated the epochs with segments exceeding the amplitude range of -100 μV to 100 μV for 4 frontal electrodes (Fp1/2, F7/8), and of -75 μV to 75 μV for the remaining 24 electrodes. Epochs containing segments of flat lines persisting for more than 100 ms were also rejected. Voltage threshold rejection criteria were applied for the entire duration of the epoch, as well as - 2000 ms pre-stimulus onset to neutralize the effect of amplifier saturation if needed. Flatline rejection criteria were applied in the -200 to 1200 EEG epoch. Participants were included in the analyses only if a minimum of 30 trials survived the artifact rejection criteria.

A single ERP was computed by averaging all EEG epochs regardless of the stimulus category and the motor response provided. To obtain measurements corresponding to the amplitude of the N400 component, the mean voltage values were extracted from the 300-700 time window for the prefrontal (Fp1/2), frontal (F7/8, F3/4, Fz), frontocentral (Fc3/4, Fcz) and frontotemporal (Ft7/8) sites, and from the 300-500 ms time window for the rest of the scalp. Due to the nature of the social role acceptance task and our interest in the decision evaluation and working memory processes associated with the social role playing, the LPP component was also analyzed. To acquire the LPP measurements, the mean voltage values were extracted from the 800-1200 ms time window for the prefrontal (Fp1/2), frontal (F7/8, F3/4, Fz), frontocentral (Fc3/4, Fcz) and frontotemporal (Ft7/8) sites, and from the 600-1200 ms time window for the rest of the scalp. Overall, the EEG/ERP

41 technique achieved the specific aim of obtaining an objective neurobiological measure that could serve as a biomarker of the placebo expectation effect.

Statistical Analysis

All analyses exploring the effect of the AP-Placebo were performed while controlling for age, level of education, social desirability, pre-experimental fatigue, Total SPQ score, and Total PDI- 21 score as covariates. The purpose of this approach was to eliminate the confounding effects of the abovementioned demographic and psychometric characteristics. For our tested participants, the percentages of accepted social roles (SRs) of each category were computed by dividing the number of accepted SRs by the total number of SRs participants responded to (i.e., the sum of acceptances and rejections), within each SR category. Subsequently, each treatment group was divided into high acceptors of extraordinary SRs (HA-ESR) and low acceptors of extraordinary SRs (LA-ESR) using the median split procedure. A similar method was used to divide participants into high and low schizotypy subgroups according to their Total SPQ score. These divisions were performed to explore whether the tendency to play ESRs as well as participants’ schizotypy profile moderate the effect of the AP-Placebo on social role acceptance.

The literature presents sufficient evidence of the association between schizotypy and the demographic characteristics that were controlled for the analysis of the AP-Placebo effect. In particular, those with higher scores for scales related to schizotypy tend to be younger (Fossatti, Raine, Carretta, Leonardi, & Maffei, 2003; Mata, Matais-Colx, & Peralta, 2005; Bora & Baysan Arabaci, 2009;) and less educated (Miettunen et al., 2010; Neill, 2014), have a lesser desire to self- represent in a socially desirable manner (Chabrol & Raynal, 2018; Ladea et al., 2020), and exhibit higher levels of fatigue and physical anhedonia (Bernstein & Riedel, 1987; Clementz, Grove, Katsanis, & Iacono, 1991; Koffel & Watson, 2010). Therefore, for the analysis of the moderation effect of the tendency to play ESRs and participants' schizotypy, we did not control for those demographic and psychometric characteristics as removing those covariates from the statistical analysis would distort our inference on the subclinical manifestation of the schizotypy construct.

Demographics and clinical characteristics of our tested samples were compared parametrically with independent-samples t-tests. Pre- and post-experimental fatigue scores were converted to the

42 percent of the maximum possible score (POMP) for standardization purposes (Cohen, Cohen, Aiken, & West, 1999) and were analyzed across sessions with the two-way analysis of variance (ANOVA). Partial Pearson’s r correlation, simple linear regression, and multiple regression analyses were run between the SPQ Total scores and the percentages of accepted SRs, with age, level of education, and social desirability used as control variables. For this analysis, our sole purpose was to replicate the results of Fernandez-Cruz et al. (2016) using similar statistical methods. Because we had a directional hypothesis about the relationship between the variables, obtained p-values will be reported as one-tailed for these tests.

A mixed-model analysis ANCOVA was separately run for the percentages of accepted SRs and the RTs. Our model had session (session 1 versus session 2), extraordinariness (ordinary versus extraordinary), and favourability (favourable versus unfavourable) as within-subjects factors, and treatment group (placebo versus no pill) as a between-subjects factor. Analysis of RTs also included a fourth factor – decision (acceptance versus rejection). Since the percentages of rejections are the reversal of the percentages of acceptances, it was not necessary to include the decision factor in the analysis of response accuracies. For the analysis of the moderation effect of the tendency to play ESRs or schizotypy, a mixed-model repeated-measures ANOVA was used, with acceptance of extraordinary social roles (A-ESR) or schizotypy subgroup (high versus low) entered as the second between-subjects factor. To explore the source of interactions, we further used univariate analyses post-hoc. For cases when no SRs were accepted within a particular category, RTs were estimated by computing the average between SR categories of the similar ‘Extraordinariness’ and ‘Favourability’ ratings.

Differences in the N400 and the LPP amplitudes were compared with three mixed-model ANCOVAs performed on each electrode subset. For the sagittal subset, session and electrode were entered as within-subjects factors, whereas treatment group – as a between-subjects factor. For the parasagittal and lateral subsets, hemiscalp (left versus right) was added as a second within-subjects factor. The ANOVA with similar factors was run to investigate the influence of the A-ESR and schizotypy subgroups on the AP-Placebo effect. ERPs were not compared across SR categories or the motor response type, as previous studies have shown that such comparison rendered barely significant differences (Fernandez-Cruz, Mohamed Ali, Bourgeais, Walpola, & Debruille, 2013).

43 Univariate analysis performed at each electrode was done post-hoc to explore the source of observed interactions.

The false discovery rate (FDR) method was used to adjust for multiple comparisons (Benjamini & Hochberg, 1995). To take into account the heterogeneous variances, Levene’s test (1960) was used for the t-tests and the Greenhouse and Geissner’s (1950) correction for the ANCOVA and the ANOVA. Effect sizes will be reported as the proportion of variance explained by the phenomenon. All statistical analyses were performed with IBM SPSS Statistics (version 23).

Results

Effect of the antipsychotic-placebo on social role acceptance

Demographic and psychometric characteristics

Demographic and psychometric characteristics of the AP-Placebo and the no pill groups are presented in Table 4. The two groups did not statistically differ in terms of sex, age, and level of education. The AP-Placebo and the no pill samples were relatively similar on schizotypy and delusion proneness characteristics as no differences were found neither for the SPQ and the PDI- 21 scores. Both groups showed a similar tendency to play ESRs as reflected by the percentage of ESRs accepted at session 1 of the task.

All participants showed a moderate degree of concern for the social desirability of their responses. The MC-SDS score was slightly lower in the AP-Placebo than in the no pill group (t(98) = -2.03, p < .05, r2 = .04). The pre-experimental fatigue level was nearly identical for both groups. Only those who took the AP-Placebo became significantly more tired from session 1 to session 2 2 of the experiment (Session x Treatment Group, F(1, 97) = 13.94, p = .0003, ηp = .13), with the post-experimental fatigue score being higher in the AP-Placebo group than in the no pill group (t(97) = 2.96, p = .004, r2 = .08).

44 Table 4 Demographic and psychometric characteristics of antipsychotic-placebo and no pill treatment groups AP-Placebo No Pill (N = 50) (N = 50) M (SD) M (SD) Sex, % Male (N) 46 (23) 44 (22) Age 22.56 (2.94) 23.22 (3.05) Years of education 14.68 (1.53) 15.26 (1.77) Total SPQ 20.26 (15.32) 17.26 (11.07) SPQ Delusion-like ideation 6.30 (6.11) 5.52 (4.57) SPQ Interpersonal 9.44 (7.57) 7.28 (5.70) SPQ Disorganization 4.52 (4.10) 4.46 (3.32) Total PDI-21 ‘Yes’ 5.96 (4.62) 5.12 (4.09) PDI-21 Distress 14.44 (14.69) 11.49 (11.75) PDI-21 Preoccupation 15.52 (15.16) 12.94 (12.39) PDI-21 Conviction 18.71 (16.29) 16.24 (14.00) MC-SDS 15.64* (5.73) 17.86 (5.19) Fatiguea (pre-experiment) 31.60 (15.49) 31.00 (17.71) Fatiguea (post-experiment) 42.47** (22.50) 30.20 (18.61) % of accepted ESRs (Session 1) 24.55 (18.54) 26.07 (21.78) Note. AP-Placebo, antipsychotic-placebo; SPQ, Schizotypal Personality Questionnaire; PDI-21, The 21-Item Peters et al. Delusions Inventory; MC-SDS, The Marlowe-Crowne Social Desirability Scale; a Fatigue score calculated using the percent of maximum possible score (POMP) (Cohen et al., 1999). *p < .05, **p < .01, *** p < .001

Consistent with the literature, there was a significant correlation between the Total SPQ scores and the following demographic and psychometric characteristics for all participants: age (r(98) = -.21, p = .02, one-tailed), level of education (r(95) = -.25, p = .007, one-tailed), pre-experimental energy (r(98) = .40, p = .00002, one-tailed), social desirability (r(98) = -.34, p = .0003, one-tailed), and Total PDI-21 score (r(95) = .72, p < .00001, one-tailed). In consequence, these parameters were controlled in all further analyses of the placebo effect.

45 Schizotypy and the tendency to play extraordinary social roles

After controlling for age, level of education, and social desirability, we saw a significant positive correlation between the SPQ Total score and the percentages of accepted extraordinary SRs at session 1 (r(92) = .30, p = .002, one-tailed) (Table 5a). This correlation was significant for both extraordinary favourable (r(92) = .25, p = .008, one-tailed) and extraordinary unfavourable SRs (r(92) = .34, p = .0003, one-tailed) but neither for ordinary unfavourable nor for ordinary favourable SRs (Table 5b). Extraordinary unfavourable SRs had the strongest association with both the SPQ Total scores and the scores for three SPQ clusters (interpersonal, delusion-like ideation, disorganization), followed by extraordinary favourable, ordinary unfavourable, and then ordinary favourable SRs. Regarding the three SPQ clusters, the strongest correlation with accepted SRs was seen for the delusion-like ideation cluster of SPQ, and the weakest – for the interpersonal cluster. This trend was uniform across all SR subcategories. For the SPQ Interpersonal score, a significant correlation was seen only for extraordinary unfavourable SRs, while the SPQ delusion- like ideation scores had a stronger association with the percentages of acceptance than the SPQ Total score for all four SR subcategories.

A similar association pattern was seen for the PDI-21 Total ‘Yes’ scores as well as the scores for three PDI-21 clusters (distress, preoccupation, conviction): extraordinary unfavourable SRs were the ones that had the strongest positive correlation, followed by extraordinary favourable, ordinary unfavourable, and then ordinary favourable SRs (Table 5a). Among all four separate PDI- 21 scores, the Distress scores had the weakest association with SR acceptance, and PDI-21 Total ‘Yes’ – the strongest. In sum, our results fully replicated the correlation pattern demonstrated by Fernandez-Cruz et al. (2016), with a smaller sample size.

46 Table 5a Pearson’s correlation coefficients between the percentages of acceptance for each social role category and the SPQ and PDI-21 scores when controlling for age, education, and social desirability Clinical scores Ordinary roles Extraordinary Favourable roles Unfavourable roles roles r p r p r p r p Total SPQ .155 .068 .298 .002 .226 .014 .291 .002 SPQ Interpersonal .011 .459 .170 .051 .084 .210 .145 .082 SPQ Delusion-like ideation .228 .014 .340 .0004 .299 .002 .329 .001 SPQ Disorganization .196 .029 .258 .006 .214 .019 .292 .002 Total PDI-21 .239 .011 .373 .0001 .307 .002 .376 .0001 PDI-21 Distress .149 .080 .262 .006 .207 .025 .265 .006 PDI-21 Preoccupation .192 .034 .308 .001 .256 .007 .305 .002 PDI-21 Conviction .240 .011 .331 .001 .282 .003 .345 .0004 Note. PDI, The 21-Item Peters et al. Delusions Inventory; SPQ, Schizotypal Personality Questionnaire. N = 97 for the SPQ and its three factors; N = 94 for the PDI-21 and its three subscales. Values in bold are statistically significant p-values at the 0.05 level (1-tailed).

Simple linear regression was performed to explore whether the percentages of SR acceptance had enough power to predict participant’s SPQ Total score. When each SR subcategory was considered alone, the percentages of accepted ordinary unfavourable (β = .23, R2 = .05, F(1, 95) = 5.09, p = .03), extraordinary favourable (β = .24, R2 = .06, F(1, 95) = 5.89, p = .02) and extraordinary unfavourable SRs (β = .37, R2 = .14, F(1, 95) = 15.09, p = .0002) were significant predictors of the SPQ Total score, while the percentages of accepted ordinary favourable (β = .13, R2 = .02, F(1, 95) = 1.53, p = .22) SRs were not (Figure 4). Additionally, the percentages of acceptance of each of the four SR subcategories accounted for a significant proportion of variance in the SPQ Total scores, as demonstrated by the multiple regression analysis (R2 = .15, F(4, 92) = 4.17, p = .004). The standardized β coefficient for each SR subcategory was as follows: extraordinary favourable (β = -.20, p = .37), extraordinary unfavourable (β = .51, p = .02), ordinary unfavourable (β = .06, p = .68), ordinary favourable (β = -.11, p = .91) SRs.

47 Table 5b Pearson’s correlation coefficients between the percentages of acceptance for each social role category combinations and the SPQ and PDI-21 scores when controlling for age, education, and social desirability Clinical scores Ordinary Ordinary Extraordinary Extraordinary favourable roles unfavourable favourable roles unfavourable roles roles r p r p r p r p Total SPQ .128 .110 .151 .074 .248 .008 .341 .0003 SPQ Interpersonal .013 .452 .016 .440 .119 .127 .229 .013 SPQ Delusion-like ideation .192 .032 .213 .019 .314 .001 .344 .0003 SPQ Disorganization .149 .076 .193 .031 .209 .022 .302 .002 Total PDI-21 .199 .029 .226 .016 .317 .001 .411 .00003 PDI-21 Distress .120 .128 .137 .097 .210 .023 .304 .002 PDI-21 Preoccupation .160 .065 .179 .045 .264 .006 .336 .001 PDI-21 Conviction .198 .030 .222 .017 .279 .004 .366 .0002 Note. PDI, The 21-Item Peters et al. Delusions Inventory; SPQ, Schizotypal Personality Questionnaire. N = 97 for the SPQ and its three factors; N = 94 for the PDI-21 and its three subscales. Values in bold are statistically significant p-values at the 0.05 level (1-tailed).

A better predictive power of accepted SRs was seen for the PDI-21 Total ‘Yes’ scores. Simple linear regression showed that the percentages of accepted ordinary unfavourable (β = .25, R2 = .06, F(1, 92) = 6.25, p = .01), extraordinary favourable (β = .31, R2 = .10, F(1, 92) = 9.88, p = .002), and extraordinary unfavourable (β = .42, R2 = .18, F(1, 92) = 19.73, p = .00003) SRs were significant predictors of the PDI-21 Total ‘Yes’ score, while the regression equation for the percentages of accepted ordinary favourable roles was approaching significance (β = .20, R2 = .04, F(1, 92) = 3.78, p = .06). A multiple regression analysis rendered a significant regression equation (F(4, 89) = 5.04, p = .001), with an R2 of .19. The standardized β coefficient for each SR subcategory was as follows: extraordinary favourable (β = -.15, p = .50), extraordinary unfavourable (β = .51, p = .01), ordinary unfavourable (β = .03, p = .85), ordinary favourable (β = .05, p = .75) SRs.

48 a c

r2 = .128 r2 = .248 p = .110 p = .008

b d

r2 = .151 r2 = .341 p = .074 p = .0003

Figure 4. Partial Pearson’s r correlation between the percentages of accepted social roles (x-axis) and the total SPQ score (y-axis) for ordinary favourable (a), ordinary unfavourable (b), extraordinary favourable (c), and extraordinary unfavourable (d) social role categories. Age, level of education, and Social Desirability Scale scores were entered as the control variables.

49 Session 1 Session 2

Ordinary 61.69% 60.35% favourable 62.64% 60.54%

Ordinary 36.79% 35.65% unfavourable 33.36% 34.35% AP-Placebo Extraordinary 31.90% 27.99% No Pill favourable 35.28% 29.67%

Extraordinary 15.47% 13.97% unfavourable 15.16% 16.07%

0 20 40 60 80 100 0 20 40 60 80 100 % of accepted social roles % of accepted social roles

Figure 5. Mean percentages of accepted social roles for the antipsychotic-placebo (N = 50) and the no pill (N = 50) groups at Session 1 (left) and Session 2 (right) of the social role acceptance task. Error bars display the standard error of the mean.

Percentages of accepted social roles

At both sessions, the placebo group did slightly better on the social role acceptance task than the no pill group, with the latter showing a marginally higher number of missed responses. At session 1, participants who took the placebo responded to 97.31% (SD = 5.88%) of presented social roles, while participants from the no pill group – to 92.82% (SD = 9.46%). From all SRs that participants responded to at the first session, the percentages of accepted SRs were 36.96% (SD = 14.33%) for the placebo group and 37.09% (SD = 16.57%) for the no pill group. A similar pattern of acceptance was observed at session 2 of the task, where the placebo group responded to 96.48% (SD = 7.57%) of presented SRs and the no pill group – to 94.23% (SD = 9.24%). From all SRs that participants responded to at the second session, the placebo group accepted, on average, 35.18% (SD = 15.01%) and the no pill group – 35.62% (SD = 19.23%). Percentages of acceptance for each of the four role subcategories (ordinary favourable, ordinary unfavourable, extraordinary favourable, extraordinary unfavourable) are displayed in Figure 5. Thus, no significant differences were observed between the placebo and the no pill groups. Similarly, no interaction with the session factor was seen.

50 In all participants, regardless of the treatment group, OSRs (M = 48.17%, SE = 1.70%) were accepted more frequently than ESRs (M = 23.19%, SE = 1.72%), and favourable SRs (M = 46.26%, SE = 1.87%) were accepted more frequently than unfavourable SRs (M = 25.10%, SE =

2 1.36%). Thus, there was a main effect of Extraordinariness (F(1, 99) = 280.96, p < .00001, ηp = 2 .74) and Favourability (F(1, 99) = 363.29, p < .00001, ηp = .79). Extraordinariness x Favourability interaction was also significant due to a greater difference between the percentages of accepted favourable and unfavourable SRs of ordinary type than the percentages of accepted favourable and

2 unfavourable SRs of extraordinary type (F(1, 99) = 63.06, p < .00001, ηp = .39). Session did not moderate the acceptance patterns for ESRs and OSRs. All participants, however, accepted favourable SRs less frequently at session 2 than at session 1 (Session x Favourability, F(1, 99) = 2 7.16, p = .009, ηp = .07). This effect was not seen for unfavourable SRs.

Reaction Times (RTs)

While controlling for participants’ age, level of education, baseline fatigue levels, social desirability, Total SPQ and Total PDI-21 scores, the mixed-model ANCOVA across sessions revealed a significant Session x Favourability x Treatment Group interaction (F(1, 92) = 5.33, p = 2 .02, ηp = .06). At session 2 of the task, the placebo group provided faster responses than the no pill group to SRs of favourable type but slower responses to SRs of unfavourable type 2 (Favourability x Treatment Group, F(1, 92) = 4.46, p = .04, ηp = .05). This was contrasting to session 1, where the placebo group was faster at providing responses to SRs of both favourable and unfavourable type. No other significant interactions with the treatment group factor were revealed, including no interaction with role extraordinariness.

Session x Favourability x Treatment Group x Decision interaction, however, was approaching 2 statistical significance (F(1, 92) = 3.40, p = .07, ηp = .04). Post-hoc analyses confirmed that Favourability x Treatment Group interaction was significant for accepted SRs at session 1 only: those who took the AP-Placebo were by 47.82 ms (SE = 22.50 ms) faster than participants of the

2 no pill group at accepting SRs of unfavourable type (F(1, 92) = 4.29, p = .04, ηp = .05). For accepted SRs of favourable type, the AP-Placebo group displayed only a 7.97 ms (SE = 20.15) faster RTs. In contrast, at session 2, no significant interaction with favourability was seen: the AP- Placebo group was by 24.62 ms (SE = 22.37 ms) faster than the no pill group at accepting favoura-

51 Accepted SRs

1060 ****

1010

AP-Placebo 960 No Pill Reaction Time (ms)

910

860 Ordinary favourable Ordinary Extraordinary Extraordinary unfavourable favourable unfavourable

Rejected SRs

**** 1060

1010

AP-Placebo 960 No Pill Reaction Time (ms)

910

860 Ordinary favourable Ordinary Extraordinary Extraordinary unfavourable favourable unfavourable

Figure 6. Mean reaction times per role category for the antipsychotic-placebo (N = 50) and the no pill (N = 50) groups across the two sessions of the social role acceptance task. Error bars display the standard error of the mean.

52 -able SRs but by 6.26 ms (SE = 23.01 ms) slower at accepting unfavourable SRs. Favourability x Treatment Group interaction was not observed for RTs corresponding to SR rejections.

N400 amplitude

The grand average event-related potentials for the AP-Placebo and the no pill groups are presented in Figure 9. For the analysis of the placebo effect on the N400 amplitude, the mean voltage values were extracted from the 300-700 ms time window for the prefrontal (Fp1/2), frontal (F7/8, F3/4, Fz), frontocentral (Fc3/4, Fcz) and frontotemporal (Ft7/8) sites, and from the 300-500 ms time window for the rest of the scalp. While controlling for participants’ age, level of education, baseline fatigue levels, Total SPQ and Total PDI-21 scores as well as social desirability bias, the mixed-model ANCOVA across sessions yielded a significant main effect of the Treatment Group 2 at all three subsets of electrodes: sagittal (F(1, 92) = 7.98, p = .006, ηp = .08), parasagittal (F(1, 2 2 96) = 9.45, p = .003, ηp = .09), and lateral (F(1, 96) = 6.52, p = .01, ηp = .07) (Table 6). No significant interactions with the session factor were seen. Those who took the AP-Placebo showed a significantly smaller N400 amplitude after seeing the SR names than those from the no pill group. This difference was maximal over centroparietal sites (Figure 7).

At the sagittal subset, the AP-Placebo group showed a significantly smaller N400 than the no pill group at Cz and Pz (Table 7). The Treatment Group x Electrode interaction was significant since no notable group differences were detected at the other two electrodes of this subset - Fz and 2 Fcz (F(1.64, 151.26) = 4.99, p = .01, ηp = .05). Regarding the parasagittal subset, a significantly smaller N400 for the AP-Placebo group was seen at C3/4, Cp3/4, and P3/4. At the lateral subset, the post-hoc tests confirmed a significantly smaller N400 among those who took the placebo at Ft8 and T4 of the right hemiscalp as well as at T7 of the left hemiscalp. Thus, no significant interaction with the hemiscalp factor was observed. At the lateral subset, the difference in the N400 amplitude between the AP-Placebo and the no pill groups was the smallest in comparison to other electrode subsets.

53 Table 6 Summary of effects of the antipsychotic-placebo on the N400 amplitude across the two sessions of the social roles task 2 Electrode subset Within-subjects factor F df p ηp

Sagittal Treatment Group 7.98 1, 92 .006 .08 Treatment Group x Electrode 4.99 1.64, 151.26 .01 .05 Treatment Group x Session 1.31 1, 92 .26 .01 Treatment Group x Session x Electrode 0.65 1.74, 159.73 .50 .007 Parasagittal Treatment Group 9.45 1, 92 .003 .09 Treatment Group x Electrode 1.63 1.91, 175.25 .20 .02 Treatment Group x Hemiscalp 0.22 1, 92 .64 .002 Treatment Group x Session 1.23 1, 92 .27 .01 Treatment Group x Electrode x Hemiscalp 0.52 3.34, 307.28 .69 .006 Treatment Group x Electrode x Session 0.43 1.67, 153.60 .61 .005 Treatment Group x Hemiscalp x Session 1.86 1, 92 .18 .02 Treatment Group x Hemiscalp x Session x 1.36 3.28, 301.81 .26 .02 Electrode Lateral Treatment Group 6.52 1, 92 .01 .07 Treatment Group x Electrode 0.51 1.28, 117.92 .52 .006 Treatment Group x Hemiscalp 0.03 1, 92 .86 < .001 Treatment Group x Session 0.42 1, 92 .52 .005 Treatment Group x Electrode x Hemiscalp 0.82 1.73, 159.02 .43 .009 Treatment Group x Electrode x Session 0.22 1.45, 133.08 .75 .002 Treatment Group x Hemiscalp x Session 0.23 1, 92 .63 .003 Treatment Group x Hemiscalp x Session x 0.81 2.39, 219.93 .47 .009 Electrode Note. Analysis of covariance (ANCOVA) performed while controlling for age, baseline fatigue levels, level of education, social desirability, Total SPQ, and Total PDI-21 scores.

54 µV

Figure 7. Interpolated scalp map of the antipsychotic-placebo effect on the N400 amplitude across the two sessions of the social role acceptance task. Values denote mean voltage difference between the AP-Placebo and the no pill groups in the N400 time window. The maximal decrease in the N400 was observed over the centroparietal electrode sites.

Table 7 Electrodes with significant main effect of the antipsychotic-placebo on the N400 amplitude Subset Electrode Statistical test

2 Sagittal Cz F (1, 92) = 10.04, p = .002, FDR-p = .008, ηp = .10 2 Pz F (1, 92) = 16.88, p = .00009, FDR-p = .002, ηp = .16

2 Parasagittal C3 F (1, 92) = 12.71, p = .0006, FDR-p = .003, ηp = .12 2 C4 F (1, 92) = 9.82, p = .002, FDR-p = .008, ηp = .10 2 Cp3 F (1, 92) = 14.33, p = .0003, FDR-p = .002, ηp = .13 2 Cp4 F (1, 92) = 15.98, p = .0001, FDR-p = .002, ηp = .15 2 P3 F (1, 92) = 11.88, p = .0009, FDR-p = .004, ηp = .11 2 P4 F (1, 92) = 14.61, p = .0002, FDR-p = .002, ηp = .14 µV 2 Lateral Ft8 F (1, 92) = 7.31, p = .008, FDR-p = .02, ηp = .07 2 T3 F (1, 92) = 7.20, p = .009, FDR-p = .02, ηp = .07 2 T4 F (1, 92) = 6.20, p = .01, FDR-p = .04, ηp = .06 Note. Post-hoc analysis of covariance (ANCOVA) performed while controlling for age, baseline fatigue levels, level of education, social desirability, Total SPQ, and Total PDI-21 scores. α = .05

55 LPP amplitude

Consistent with the strategy used to analyze the effect of placebo on the N400 amplitude, for the LPP, the mean voltage values were extracted from the 800-1200 ms time window for the prefrontal (Fp1/2), frontal (F7/8, F3/4, Fz), frontocentral (Fc3/4, Fcz) and frontotemporal (Ft7/8) sites, and from the 600-1200 ms time window for the rest of the scalp. In brief, the largest difference between the AP-Placebo and the no pill groups with regard to the LPP amplitude was observed over temporal sites, with a greater effect over the right hemiscalp (Figures 8 and 9). The mixed-model ANCOVA across sessions revealed a significant Session x Treatment Group

2 interaction for all three electrode subsets: sagittal (F(1, 92) = 13.54, p = .0004, ηp = .13), 2 2 parasagittal (F(1, 92) = 14.08, p = .0004, ηp = .13), and lateral (F(1, 92) = 13.05, p = .0005, ηp = .12) (Table 8). This suggests that the placebo effect became more profound in session 2 of the task.

2 For the parasagittal (F(1, 92) = 6.45, p = .01, ηp = .07) and the lateral (F(1, 92) = 17.27, p = 2 .00007, ηp = .16) subsets, post-hocs confirmed the main effect of the Treatment Group at session 2. The AP-Placebo group displayed a significantly bigger LPP than the no pill group at Cp4 of the parasagittal subset as well as at Ft8, T4, and Tp8 of the lateral subset (Table 9). This effect was also detected at neighbouring P4, T6, and O2, but it was non-significant after the FDR adjustment. At session 1, no significant differences between the two treatment groups were observed.

At the parasagittal subset, the difference between the treatment groups was bigger over the right hemiscalp than over the left hemiscalp, so a significant Treatment Group x Hemiscalp 2 interaction was seen, for both sessions (F(1, 92) = 4.88, p = .03, ηp = .05). At the lateral subset, no interaction with the hemiscalp factor was detected as the placebo-induced increase in the LPP amplitude was observed not solely over the right hemiscalp, but also over the left hemiscalp, namely at T3 and Tp7. At these electrode sides, the main effect of treatment group was approaching statistical significance after the adjustment for multiple comparisons.

56 Table 8 Summary of the effects of the antipsychotic-placebo on the LPP amplitude across the two sessions of the social roles task 2 Electrode subset Within-subjects factor F df p ηp Sagittal Treatment Group 0.23 1, 92 .64 .002 Treatment Group x Electrode 0.29 1.24, 114.22 .64 .003 Treatment Group x Session 13.54 1, 92 .0004 .13 Treatment Group x Session x Electrode 0.11 1.29, 118.67 .80 .001 Parasagittal Treatment Group 1.18 1, 92 .28 .01 Treatment Group x Electrode 0.99 1.76, 161.43 .37 .01 Treatment Group x Hemiscalp 4.88 1, 92 .03 .05 Treatment Group x Session 14.08 1, 92 .0003 .13 Treatment Group x Electrode x Hemiscalp 0.78 2.45, 225.44 .48 .008 Treatment Group x Electrode x Session 0.19 1.72, 158.30 .79 .002 Treatment Group x Hemiscalp x Session 0.004 1, 92 .95 < .001 Treatment Group x Hemiscalp x Session x 1.29 2.89, 265.88 .28 .01 Electrode Lateral Treatment Group 9.72 1, 92 .002 .10 Treatment Group x Electrode 0.54 1.32, 121.36 .51 .006 Treatment Group x Hemiscalp 1.27 1, 92 .26 .01 Treatment Group x Session 13.05 1, 92 .0005 .12 Treatment Group x Electrode x Hemiscalp 1.47 1.36, 125.15 .23 .02 Treatment Group x Electrode x Session 1.04 1.36, 125.32 .33 .01 Treatment Group x Hemiscalp x Session 0.37 1, 92 .54 .004 Treatment Group x Hemiscalp x Session x 0.14 1.82, 167.52 .85 .002 Electrode Note. LPP, late positive potential. Analysis of covariance (ANCOVA) performed while controlling for age, baseline fatigue levels, level of education, social desirability, Total SPQ, and Total PDI-21 scores.

57 Session 1 Session 2

µV µV

Figure 8. Interpolated scalp map of the antipsychotic-placebo effect on the LPP amplitude at Session 1 and Session 2 of the social role acceptance task. Values denote mean voltage difference between the AP-Placebo and the no pill groups in the LPP time window. The maximal increase in the LPP was observed over the right lateral hemiscalp at session 2.

Table 9 Electrodes with significant main effect of the antipsychotic-placebo on the LPP amplitude Subset Electrode Statistical test Session 1 2 Parasagittal Cp4 F (1, 92) = 0.86, p = .36, FDR-p = .99, ηp = .009 2 Lateral Ft8 F (1, 92) = 1.89, p = .17, FDR-p = .96, ηp = .02 2 T4 F (1, 92) = 5.72, p = .02, FDR-p = .26, ηp = .06 2 Tp8 F (1, 92) = 5.72, p = .02, FDR-p = .26, ηp = .06 Session 2 2 Parasagittal Cp4 F (1, 92) = 8.05, p = .006, FDR-p = .04, ηp = .08 2 Lateral Ft8 F (1, 92) = 7.89, p = .006, FDR-p = .04, ηp = .08 2 T4 F (1, 92) = 13.26, p = .0004, FDR-p = .01, ηp = .13 2 Tp8 F (1, 92) = 11.73, p = .0009, FDR-p = .01, ηp = .11 Note. Bold values denote statistical significance after the FDR correction, α = .05

58 Session 1 AP-Placebo No Pill

Session 2

Figure 9. Grand average event-related potentials for the antipsychotic-placebo (N = 50) and the no pill (N = 50) groups in the social role acceptance task.

59 Tendency to play extraordinary social roles and antipsychotic-placebo

Demographic and psychometric characteristics

Table 10 Demographic and psychometric characteristics of high (HA-ESR) and low (LA-ESR) acceptors of extraordinary social roles HA-ESR LA-ESR AP-Placebo No Pill AP-Placebo No Pill (N = 25) (N = 25) (N = 25) (N = 25) M (SD) M (SD) M (SD) M (SD) Sex, % Male (N) 44 (11) 60 (15) 48 (12) 28 (7) Age 22.08 (2.60) 22.84 (3.35) 23.04 (3.23) 23.60 (2.72) Years of education 14.46 (1.53) 14.68 (1.84) 14.91* (1.54) 15.84 (1.52) Total SPQ 25.28 (16.11) 19.56 (11.78) 15.24 (12.92) 14.96 (10.01) SPQ Delusion-like ideation 8.24 (6.72) 6.64 (4.97) 4.36 (4.80) 4.40 (3.93) SPQ Interpersonal 11.12 (7.26) 8.04 (5.76) 7.76 (7.64) 6.52 (5.64) SPQ Disorganization 5.92 (4.63) 4.88 (3.48) 3.12 (2.98) 4.04 (3.16) Total PDI-21 ‘Yes’ 7.42 (4.85) 6.40 (4.51) 4.50 (3.96) 3.79 (3.16) PDI-21 Distress 17.88 (15.84) 14.56 (13.42) 11.00 (12.86) 8.29 (8.89) PDI-21 Preoccupation 19.46 (17.14) 16.56 (14.04) 11.58 (11.97) 9.17 (9.26) PDI-21 Conviction 23.42 (17.99) 20.52 (15.34) 14.00 (13.12) 11.79 (11.10) MC-SDS 15.48 (5.37) 17.48 (5.63) 15.80 (6.18) 18.24 (4.79) Fatiguea (pre-experiment) 33.17 (13.94) 32.10 (20.00) 30.03 (17.05) 29.90 (15.42) Fatiguea (post-experiment) 47.49** (21.36) 32.00 (19.08) 37.47 (22.90) 28.33 (18.32) % of accepted ESRs (Session 1) 38.61 (16.19) 43.50 (17.81) 10.48 (5.20) 8.65 (4.36) Note. AP-Placebo, antipsychotic-placebo; HA-ESR, high acceptors of extraordinary social roles; LA-ESR, low acceptors of extraordinary social roles; SPQ, Schizotypal Personality Questionnaire; PDI-21, The 21-Item Peters et al. Delusions Inventory; MC-SDS, The Marlowe-Crowne Social Desirability Scale; a Fatigue score calculated using the percent of maximum possible score (POMP) (Cohen et al., 1999). *p < .05, **p < .01

Table 10 shows the demographic and psychometric characteristics of the placebo and the no pill groups subdivided into high (HA-ESR) and low (LA-ESR) acceptors of extraordinary social roles according to the median split procedure. No significant differences were observed between the treatment groups in sex distribution and participants’ age. Due to the low variance in the number of years of education, LA-ESRs who took the placebo had a significantly lower number of completed schooling in comparison to LA-ESR of the no pill group participants (t(46) = -2.10,

60 p = .04, r2 = .09). Interestingly, among HA-ESR participants, the AP-Placebo group had a higher SPQ Total score than the no pill group, although such a difference was non-significant. This phenomenon, nevertheless, was not seen among LA-ESR participants.

All participants did not differ in their scores for social desirability and baseline fatigue levels. Post-experimental fatigue score, however, was significantly higher in the AP-Placebo group among HA-ESRs only (t(48) = 2.70, p = .009, r2 = .13). Nevertheless, we observed no significant Treatment Group x A-ESR interaction for the change in fatigue levels from session 1 to session 2.

Percentages of accepted social roles

Since the percentages of accepted ESRs at session 1 were used to subdivide our treatment group samples into high and low acceptors using median split, as expected, the mixed-model repeated measures ANOVA across the two sessions of the task yielded the overall main effect of 2 A-ESR Group (F(1, 96) = 103.80, p < .00001, ηp = .52) as well as Extraordinariness x

2 Favourability x A-ESR interaction (F(1, 96) = 17.41, p = .00007, ηp = .15). Those classified as HA-ESR (M = 46.55%, SE = 1.51%) accepted a greater percentage of presented SRs than those classified as LA-ESR (M = 24.81%, SE = 1.51%). This was observed for all 4 subcategories of SRs: ordinary favourable (HA-ESR, M = 71.23%, SE = 2.30%; LA-ESR, M = 51.38%, SE = 2.30%), ordinary unfavourable (HA-ESR, M = 43.16%, SE = 2.15%; LA-ESR, M = 26.92%, SE = 2.15%), extraordinary favourable (HA-ESR, M = 47.32%, SE = 2.09%; LA-ESR, M = 15.10%, SE = 2.09%), and extraordinary unfavourable (HA-ESR, M = 24.49%, SE = 1.38%; LA-ESR, M = 5.84%, SE = 1.38%).

Additionally, we found the overall significant A-ESR x Treatment Group interaction (F(1, 96) 2 = 6.06, p = .02, ηp = .06) for the SR acceptances pattern across the two sessions of the task (Figure 10). Post-hocs confirmed that this interaction was significant for ESRs of both favourable and unfavourable type but not for any OSRs (Extraordinary favourable, F(1, 96) = 7.08, p = .009, FDR- 2 2 p = .03, ηp = .07; Extraordinary unfavourable, F(1, 96) = 5.91, p = .02, FDR-p = .03, ηp = .06). Task session did not moderate this relationship significantly. Among HA-ESRs, those who took the AP-Placebo accepted fewer ESRs than participants from the no pill group: extraordinary favourable (AP-Placebo, M = 42.12%, SE = 2.96%; No Pill, M = 52.52%, SE = 2.96%),

61

80 70 **** 60 ** Ordinary 50 favourable 40 **** * **** 30 **** Ordinary unfavourable 20 Extraordinary **** **** % of accepted social roles 10 favourable Extraordinary unfavourable 0 HA-ESR LA-ESR HA-ESR LA-ESR

Figure 10. A-ESR x Treatment Group interaction for the percentages of accepted social roles across the two sessions of the social role acceptance task. The interaction was significant for extraordinary SRs but not for ordinary SRs. Error bars display the standard error of the mean. Note: A-ESR, acceptance of extraordinary social roles; HA-ESR, high acceptors of extraordinary social roles; LA-ESR, low acceptors of extraordinary social roles; * p < .05, ** p < .01, *** p < .001, **** p < .0001. extraordinary unfavourable (AP-Placebo, M = 21.68%, SE = 1.95%; No Pill, M = 27.31%, SE = 1.95%). Among LA-ESRs, in contrast, the average percentage of ESRs accepted by the AP- Placebo group was bigger than that by the no pill group: extraordinary favourable (AP-Placebo, M = 17.77%, SE = 2.96%; No Pill, M = 12.43%, SE = 2.96%), extraordinary unfavourable (AP- Placebo, M = 7.76%, SE = 1.95%; No Pill, M = 3.92%, SE = 1.95%). For SRs of ordinary type, we saw a similar pattern of acceptance that was non-significant but nonetheless explains the absence of any interaction between the A-ESR and Treatment Group with the Extraordinariness factor.

Session x Favourability x A-ESR x Treatment Group interaction was also significant (F(1, 96) 2 = 10.95, p = .001, ηp = .10). At session 1, HA-ESRs who took the placebo accepted favourable SRs less frequently than HA-ESRs of the no pill group. For unfavourable SRs, the pattern of

62 acceptance did not differ between the two treatment groups. Among LA-ESRs, in contrast, those who took the placebo accepted both favourable and unfavourable SRs more frequently than the no pill group. Thus, the overall Favourability A-ESR x Treatment Group interaction was significant

2 in the first session of the task (F(1, 96) = 4.70, p = .03, ηp = .05). At session 2, the AP-Placebo group accepted both favourable and unfavourable SRs less frequently than the no pill group in HA-ESR participants, and more frequently in LA-ESR participant. Role favourability ratings did not moderate this relationship.

Reaction Times (RTs)

Omnibus mixed-model repeated-measures ANOVA with the tendency to play ESRs as the second between-subjects factor yielded a significant Decision x A-ESR interaction (F(1, 96) = 2 73.23, p < .00001, ηp = .43). In all subjects, regardless of the treatment group, HA-ESRs were faster at accepting and slower at rejecting SRs than LA-ESRs, with a greater difference between the two A-ESR subgroups seen for rejection responses. Post-hoc tests confirmed the main effect of A-ESR subgroup for the rejection of all four SR categories: ordinary favourable (F(1, 96) =

2 7.06, p = .009, FDR-p = .02, ηp = .10), ordinary unfavourable (F(1, 96) = 11.21, p = .001, FDR-p 2 2 = .003, ηp = .10), extraordinary favourable (F(1, 96) = 25.30, p < .00001, FDR-p = .00002, ηp = 2 .21), extraordinary unfavourable (F(1, 96) = 18.86, p = .00003, FDR-p = .0001, ηp = .16). As such, the difference between HA-ESRs and LA-ESRs was bigger for ESRs than for OSRs

2 (Extraordinariness x Decision x A-ESR, F(1, 96) = 10.31, p = .002, ηp = .10). No main effect of A-ESR subgroup was observed for SR acceptances. Moreover, no moderation by task session was seen.

We did not observe the overall Treatment Group x A-ESR interaction but instead saw a 2 significant Decision x Treatment Group x A-ESR interaction (F(1, 96) = 7.05, p = .009, ηp = .07) (Figure 11). This suggests that the moderation of the placebo effect by participants’ tendency to play ESRs was dependent on whether SRs were accepted or rejected. The task session did not have any influence on this relationship. Among HA-ESRs, the AP-Placebo group was only by 3.84 ms (SE = 29.18 ms) slower than the no pill group at accepting SRs but was by 27.49 ms (SE = 30.34 ms) faster at rejecting SRs. The opposite was seen among LA-ESRs, where the AP-Placebo group

63 SR Acceptances SR Rejections AP-Placebo No Pill

Ordinary Ordinary 1100 1100

1050 1050 ** 1000 1000 n.s.

950 950

900 900 Reaction Time (ms) Reaction Time (ms) 850 850

800 800 HA-ESR LA-ESR HA-ESR LA-ESR

Extraordinary Extraordinary 1100 1100

1050 1050

1000 1000

950 950 **** * 900 900 Reaction Time (ms) Reaction Time (ms) 850 850

800 800 HA-ESR LA-ESR HA-ESR LA-ESR

Figure 11. Effect of the antipsychotic-placebo and Decision x Treatment group x A-ESR group interaction effect on the mean reaction times (RTs) for ordinary and extraordinary social roles across the two sessions of the social role acceptance task. Error bars represent the standard error of the mean. Note: A-ESR, acceptance of extraordinary social roles; HA-ESR, high acceptors of extraordinary social roles; LA-ESR, low acceptors of extraordinary social roles; * p < .05, ** p < .01, *** p < .001, **** p < .0001.

64 was by 20.58 ms (SE = 29.18 ms) faster than the no pill group at accepting SRs but was by 32.74 ms (SE = 30.34 ms) slower at rejecting SRs. As such, the Decision x Treatment Group interaction 2 was significant among those with the low tendency to play ESRs (F(1, 48) = 5.77, p = .02, ηp = .11). No significant interactions with Extraordinariness or Favourability factors were found.

N400 amplitude

Figures 14a and 14b show the grand average event-related potentials for high and low ESR acceptors after they responded to SRs presented on the computer screen. For several participants, the N400 was characterized by a more prolonged latency. For the statistical analysis, we thus extracted the mean voltages from the 300-700 ms time window for the prefrontal (Fp1/2), frontal (F7/8, F3/4, Fz), frontocentral (Fc3/4, Fcz) and frontotemporal (Ft7/8) sites, and from the 300-500 ms time window for the rest of the scalp. In general, upon considering participants’ tendency to accept ESRs, we observed the AP-Placebo group displaying a reduction in the N400 amplitude over centroparietal and parietal sites in both high and low ESR acceptors (Figures 12, 14a, and 14b). Among HA-ESRs, the maximal difference between the two treatment groups was observed at the central sites, namely at Cz, and at the right frontotemporal sites, namely at Ft8. Among LA- ESRs, the maximal reduction in the N400 was seen at Pz. Between those with high versus those with low propensity to play ESRs, we saw a contrasting response to the AP-Placebo at the prefrontal and the frontal sites: while HA-ESRs who took the placebo exhibited a marked reduction in the N400 amplitude, LA-ESRs showed a bigger and a more prolonged N400. In sum, electrophysiologically, the brain of HA-ESRs responded to the AP-Placebo in a more diffuse fashion, with the N400 reduction seen across multiple sites across the scalp. Among LA-ESRs, contrarily, the placebo effect was predominantly localized over centroparietal and parietal electrodes.

The mixed-model ANOVA across sessions did not reveal a significant main effect of A-ESR at the sagittal and parasagittal subset, while at the lateral subset it was barely significant (F(1, 96)

2 2 = 3.99, p < .05, ηp = .04) (Table 11). Instead, at the sagittal (F(1.66, 159.17) = 4.58, p = .02, ηp 2 = .05) and the parasagittal (F(1.99, 191.13) = 3.47, p = .03, ηp = .04) subsets, we saw a significant A-ESR x Electrode interaction. At the prefrontal (Fp1/2), frontal (F7/8, F4/3, Fz), and frontotemporal (Ft7/8) sites, all HA-ESR participants displayed a bigger N400 than all LA-ESRs,

65 regardless of the treatment group. This was not the case for the rest of the scalp and explains the abovementioned interaction. After the adjustment for multiple comparisons, however, the post- hoc analyses did not confirm the significance of the main effect of A-ESR at the aforesaid electrode sides.

With regard to the effect of the AP-Placebo, we saw a significant overall A-ESR x Treatment 2 Group interaction for the sagittal subset (F(1, 96) = 4.12, p < .05, ηp = .04), an A-ESR x Electrode

2 x Treatment Group interaction for the parasagittal subset (F(1.99, 191.13) = 6.04, p = .003, ηp = .06) and an A-ESR x Electrode x Hemiscalp x Treatment Group interaction for the lateral subset 2 (F(1.74, 166.54) = 4.04, p = .02, ηp = .04). At certain electrode sites, in comparison to the no pill group, participants who took the placebo displayed a reduced amplitude of the N400 if they had a high tendency to play ESRs but showed unchanged or increased N400 amplitude if they had a low tendency to play ESRs. A significant Treatment Group x A-ESR interaction was confirmed at Fp1/2, F4, F8, and Ft8 (Table 12). All interactions with the session factor were non-significant.

At all electrodes of the sagittal subset, HA-ESRs of the AP-Placebo group showed a significantly smaller N400 amplitude relative to HA-ESRs of the no pill group (Table 13). Among LA-ESRs, the significant N400 reduction was observed at Pz only, with a smaller effect size than that seen in HA-ESRs. A similar phenomenon was observed for HA-ESRs who took the AP- Placebo at all parasagittal electrodes (Fp1/2, F3/4, Fc3/4, C3/4, Cp3/4, P3/4), with the exception of occipital O1 and O2. The biggest reduction in the N400 amplitude was seen over central (C3/4) and centroparietal (Cp3/4) sites, as well as at the prefrontal Fp2. Among LA-ESRs, the AP-Placebo group demonstrated a smaller N400 relative to the no pill group at Cp3 and P3/4 only. At Fp1/2, LA-ESRs showed increased N400 amplitude in response to placebo but the main effect of the treatment group was non-significant at these electrode sites. Concerning the lateral subset, the AP- Placebo group showed a smaller N400 at the right F8, Ft8, and T4 as well as the left T3 among HA-ESRs only. The biggest reduction in N400 was seen at the right frontal (F8) and frontotemporal (Ft8) sites. LA-ESRs, in contrast, showed increased N400 amplitude at F8 but no significant main effect of the treatment group was confirmed. At all other electrodes, no significantly smaller N400 was seen between the AP-Placebo and the no pill groups for low ESR acceptors.

66 Table 11 Summary of effects of the tendency to play extraordinary social roles on the N400 amplitude 2 Electrode subset Within-subjects factor F df p ηp Sagittal A-ESR 2.21 1, 96 .14 .02 A-ESR x Treatment Group 4.12 1, 96 < .05 .04 A-ESR x Electrode 4.58 1.66, 159.17 .02 .05 A-ESR x Electrode x Treatment Group 2.58 1.66, 159.17 .09 .03 A-ESR x Session 1.72 1, 96 .19 .02 A-ESR x Session x Treatment Group 2.37 1, 96 .13 .02 A-ESR x Session x Electrode 0.37 1.72, 164.70 .66 .004 Parasagittal A-ESR 3.19 1, 96 .08 .03 A-ESR x Treatment Group 3.40 1, 96 .07 .03 A-ESR x Electrode 3.47 1.99, 191.13 .03 .04 A-ESR x Electrode x Treatment Group 6.04 1.99, 191.13 .003 .06 A-ESR x Hemiscalp 2.94 1, 96 .09 .03 A-ESR x Hemiscalp x Treatment Group 1.98 1, 96 .16 .02 A-ESR x Session 0.96 1, 96 .33 .01 A-ESR x Session x Treatment Group 2.32 1, 96 .13 .02 A-ESR x Session x Electrode 1.50 1.65, 158.74 .23 .02 A-ESR x Session x Hemiscalp 0.61 1, 96 .44 .006 A-ESR x Electrode x Hemiscalp 1.04 3.34, 320.38 .38 .01 A-ESR x Electrode x Hemiscalp x Treatment 1.06 3.34, 320.38 .37 .01 Group Lateral A-ESR 3.99 1, 96 < .05 .04 A-ESR x Treatment Group 2.56 1, 96 .11 .03 A-ESR x Electrode 2.88 1.27, 122.09 .08 .03 A-ESR x Electrode x Treatment Group 3.34 1.27, 122.09 .06 .03 A-ESR x Hemiscalp 0.13 1, 96 .72 .001 A-ESR x Hemiscalp x Treatment Group 1.66 1, 96 .20 .02 A-ESR x Session 0.73 1, 96 .39 .008 A-ESR x Session x Treatment Group 2.85 1, 96 .10 .03 A-ESR x Session x Electrode 0.12 1.46, 140.10 .82 .001 A-ESR x Session x Hemiscalp 2.03 1, 96 .16 .02 A-ESR x Electrode x Hemiscalp 1.62 1.74, 166.54 .20 .02 A-ESR x Electrode x Hemiscalp x 4.04 1.74, 166.54 .02 .04 Treatment Group Note. A-ESR, acceptance of extraordinary social roles.

67 HA-ESR LA-ESR

µV µV

Figure 12. Interpolated scalp map of the antipsychotic-placebo effect on the N400 amplitude in high (HA-ESR) and low (LA-ESR) acceptors of extraordinary social roles across the two sessions of the social role acceptance task. Values denote mean voltage difference between the AP-Placebo and the no pill groups in the N400 time window. The effect of placebo was more profound in HA- ESR participants than in LA-ESR participants.

Table 12 Electrodes with significant antipsychotic-placebo x tendency to play extraordinary social roles interaction effect on the N400 amplitude Subset Electrode Statistical test

2 Parasagittal Fp2 F (1, 96) = 11.52, p = .001, FDR-p = .01, ηp = .11

2 Fp1 F (1, 96) = 8.56, p = .004, FDR-p = .04, ηp = .08

2 F4 F (1, 96) = 7.75, p = .006, FDR-p = .04, ηp = .07

2 Lateral F8 F (1, 96) = 11.61, p = .001, FDR-p = .01, ηp = .11

2 Ft8 F (1, 96) = 7.99, p = .006, FDR-p = .04, ηp = .08

Note. α = .05

68 Table 13 Electrodes with significant main effect of the antipsychotic-placebo on the N400 amplitude in high versus low acceptors of extraordinary social roles Subset Electrode HA-ESR, df (1, 48) LA-ESR, df (1, 48)

2 2 Sagittal Fz F = 8.11, p = .006, FDR-p = .03, ηp = .14 F = 0.25, p = .62, FDR-p = .71, ηp = .005

2 2 Fcz F = 6.20, p = .02, FDR-p = .04, ηp = .11 F = 0.22, p = .64, FDR-p = .72, ηp = .004

2 2 Cz F = 14.75, p = .0004, FDR-p = .007, ηp = .24 F = 0.68, p = .41, FDR-p = .55, ηp = .01

2 2 Pz F = 10.25, p = .002, FDR-p = .01, ηp = .18 F = 8.60, p = .005, FDR-p = .02, ηp = .15

2 2 Parasagittal Fp2 F = 10.98, p = .002, FDR-p = .01, ηp = .19 F = 2.38, p = .13, FDR-p = .21, ηp = .05

2 2 Fp1 F = 6.64, p = .01, FDR-p = .04, ηp = .12 F = 2.43, p = .13, FDR-p = .21, ηp = .05

2 2 F4 F = 10.59, p = .002, FDR-p = .01, ηp = .18 F = 0.46, p = .50, FDR-p = .61, ηp = .01

2 2 F3 F = 6.03, p = .02, FDR-p = .04, ηp = .11 F < 0.001, p = .99, FDR-p = .99, ηp < .001

2 2 Fc4 F = 8.03, p = .007, FDR-p = .03, ηp = .14 F = 0.007, p = .93, FDR-p = .96, ηp < .001

2 2 Fc3 F = 5.72, p = .02, FDR-p < .05, ηp = .11 F = 0.46, p = .50, FDR-p = .61, ηp = .009

2 2 C4 F = 10.67, p = .002, FDR-p = .01, ηp = .18 F = 1.63, p = .21, FDR-p = .31, ηp = .03

2 2 C3 F = 11.71, p = .001, FDR-p = .01, ηp = .20 F = 3.36, p = .07, FDR-p = .14, ηp = .07

2 2 Cp4 F = 12.98, p = .0007, FDR-p = .01, ηp = .21 F = 4.69, p = .04, FDR-p = .08, ηp = .09

2 2 Cp3 F = 10.04, p = .003, FDR-p = .01, ηp = .17 F = 6.23, p = .02, FDR-p = .04, ηp = .11

2 2 P4 F = 9.27, p = .004, FDR-p = .02, ηp = .16 F = 7.11, p = .01, FDR-p = .03, ηp = .13

2 2 P3 F = 7.14, p = .01, FDR-p = .03, ηp = .13 F = 6.50, p = .01, FDR-p = .04, ηp = .12

2 2 Lateral F8 F = 14.73, p = .0004, FDR-p = .007, ηp = .23 F = 1.40, p = .24, FDR-p = .34, ηp = .03

2 2 Ft8 F = 17.71, p = .0001, FDR-p = .006, ηp = .27 F = 0.05, p = .83, FDR-p = .88, ηp < .001

2 2 T4 F = 10.88, p = .002, FDR-p = .01, ηp = .18 F = 0.63, p = .43, FDR-p = .56, ηp = .01

2 2 T3 F = 6.13, p = .02, FDR-p = .04, ηp = .11 F = 2.74, p = .10, FDR-p = .18, ηp = .05

Note. HA-ESR, high acceptors of extraordinary social roles; LA-ESR, low acceptors of extraordinary social roles. Bold values denote statistical significance after the FDR correction, α = .05

LPP amplitude

Interpolated scalp maps of the placebo versus the no pill group difference in mean voltages corresponding to the LPP are presented in Figure 13. Taking everything into consideration, HA- ESR participants displayed an increased LPP amplitude in response to placebo at prefrontal, frontotemporal, and temporal sites of the right hemiscalp. LA-ESR participants, in contrast,

69 showed a more generalized increase in the LPP amplitude uniformly distributed across temporal and posterior sites of both the left and the right hemiscalp. At the prefrontal sites (Fp1/2), the AP- Placebo group exhibited a bigger LPP than the no pill group among HA-ESRs but a smaller LPP among LA-ESRs. A-ESR x Treatment Group interaction at these electrode sites, however, was non-significant.

The mixed-model ANOVA run on the mean voltages did not reveal a significant main effect of ESR acceptance nor any significant interactions between ESR acceptance and the treatment group (Table 14). Additionally, no interactions with the session factor were detected. However, we saw a significant A-ESR x Electrode interaction at all three electrode subsets: sagittal (F(1.26, 2 2 121.30) = 4.62, p = .03, ηp = .05), parasagittal (F(1.79, 172.09) = 3.60, p = .03, ηp = .04), and

2 lateral (F(1.35, 129.16) = 4.54, p = .02, ηp = .05). This suggests that the main effect of A-ESR was significant at specific electrode sites rather than distributed uniformly across the entire subset. After performing the correction for multiple comparisons, post-hoc tests confirmed a significantly bigger LPP among HA-ESRs relative to LA-ESRs at T3 and Tp7 of the lateral subset (T3, F(1,

2 2 96) = 10.48, p = .002, FDR-p = .03, ηp = .10; Tp7, F(1, 96) = 10.08, p = .002, FDR-p = .03, ηp = .10). This effect was approaching significance at Cz of the sagittal subset; C3/4, Cp3/4, and P3/4 of the parasagittal subset; and T5 of the lateral subset. For the parasagittal (F(1, 96) = 6.75, p = 2 2 .01, ηp = .07) and the lateral (F(1, 96) = 4.61, p = .03, ηp = .05) subsets, the A-ESR x Hemiscalp interaction was significant as the main effect of ESR acceptance was greater over the left hemiscalp than the right hemiscalp.

We further performed additional post-hoc tests to identify electrode sites with possible differences in the LPP amplitude between HA-ESRs and LA-ESRs after both groups received the AP-Placebo. At session 2, among high ESR acceptors, the AP-Placebo group displayed a marginally bigger LPP than the no pill group at several electrodes of the right hemiscalp, notably at F4 of the parasagittal subset and at Ft8, T4, and Tp8 of the lateral subset. Among low ESR acceptors, a bigger LPP in the placebo group was seen at C3/4 and Cp3/4 of the parasagittal subset and T3/4, Tp7/8, T5/6 of the lateral subset. FDR adjustment, however, rendered the main effect of the treatment group non-significant at all the abovementioned electrode sites for both HA-ESRs and LA-ESRs.

70 Table 14 Summary of effects of the tendency to play extraordinary social roles on the LPP amplitude 2 Electrode subset Within-subjects factor F df p ηp Sagittal A-ESR 0.42 1, 96 .52 .004 A-ESR x Treatment Group 0.03 1, 96 .86 < .001 A-ESR x Electrode 4.62 1.26, 121.30 .03 .05 A-ESR x Electrode x Treatment Group 0.56 1.26, 121.30 .50 .006 A-ESR x Session < .01 1, 96 > .99 < .001 A-ESR x Session x Treatment Group 0.52 1, 96 .47 .005 A-ESR x Session x Electrode 0.42 1.32, 126.60 .57 .004 Parasagittal A-ESR 1.14 1, 96 .29 .01 A-ESR x Treatment Group 0.02 1, 96 .90 < .001 A-ESR x Electrode 3.60 1.79, 172.09 .03 .04 A-ESR x Electrode x Treatment Group 1.73 1.79, 172.09 .18 .02 A-ESR x Hemiscalp 6.75 1, 96 .01 .07 A-ESR x Hemiscalp x Treatment Group 0.98 1, 96 .33 .01 A-ESR x Session 0.63 1, 96 .43 .007 A-ESR x Session x Treatment Group 0.02 1, 96 .89 < .001 A-ESR x Session x Electrode 0.83 1.71, 164.01 .42 .009 A-ESR x Session x Hemiscalp 1.37 1, 96 .25 .01 A-ESR x Electrode x Hemiscalp 2.51 2.46, 236.42 .07 .03 A-ESR x Electrode x Hemiscalp x Treatment 0.64 2.46, 236.42 .56 .007 Group Lateral A-ESR 2.13 1, 96 .15 .02 A-ESR x Treatment Group 0.10 1, 96 .75 .001 A-ESR x Electrode 4.54 1.35, 129.16 .02 .05 A-ESR x Electrode x Treatment Group 1.71 1.35, 129.16 .19 .02 A-ESR x Hemiscalp 4.61 1, 96 .03 .05 A-ESR x Hemiscalp x Treatment Group 0.65 1, 96 .42 .007 A-ESR x Session 0.20 1, 96 .66 .002 A-ESR x Session x Treatment Group 0.03 1, 96 .86 < .001 A-ESR x Session x Electrode 0.45 1.39, 133.61 .57 .005 A-ESR x Session x Hemiscalp 0.99 1, 96 .32 .01 A-ESR x Electrode x Hemiscalp 0.18 1.36, 130.49 .75 .002 A-ESR x Electrode x Hemiscalp x Treatment 0.63 1.36, 130.49 .48 .007 Group Note. A-ESR, acceptance of extraordinary social roles

71 HA-ESR LA-ESR Session 1

µV µV

Session 2

µV µV

Figure 13. Interpolated scalp map of the antipsychotic-placebo effect on the LPP amplitude in high (HA-ESR) and low (LA-ESR) acceptors of extraordinary social roles at Session 1 (top) and Session 2 (bottom) of the social role acceptance task. Values denote mean voltage difference between the AP-Placebo and the no pill groups in the LPP time window. A notable effect of session was observed, with the increase in LPP amplitude seen by session 2 in both HA-ESR and LA-ESR subgroups. The effect of placebo was localized anteriorly in HA-ESRs and posteriorly in LA- ESRs.

72 High acceptors of extraordinary SRs (HA-ESR) AP-Placebo No Pill

Low acceptors of extraordinary SRs (LA-ESR)

Figure 14a. Effect of the antipsychotic-placebo on event-related potentials for high (top) and low (bottom) acceptors of extraordinary social roles at Session 1 of the social role acceptance task.

73 High acceptors of extraordinary SRs (HA-ESR) AP-Placebo No Pill

Low acceptors of extraordinary SRs (LA-ESR)

Figure 14b. Effect of the antipsychotic-placebo on event-related potentials for high (top) and low (bottom) acceptors of extraordinary social roles at Session 2 of the social role acceptance task.

74 Schizotypy and antipsychotic-placebo

Demographic and psychometric characteristics

Table 15 Demographic and psychometric characteristics of participants with high and low schizotypy according to the Total SPQ score High schizotypy Low schizotypy AP-Placebo No Pill AP-Placebo No Pill (N = 25) (N = 25) (N = 25) (N = 25) M (SD) M (SD) M (SD) M (SD) Sex, % Male (N) 40 (10) 44 (11) 52 (13) 44 (11) Age 22.36 (2.61) 22.68 (3.04) 22.76 (3.28) 23.76 (3.02) Years of education 14.48 (1.59) 14.84 (1.84) 14.88 (1.48) 15.68 (1.63) Total SPQ 32.40* (11.77) 27.00 (5.07) 8.12 (5.79) 7.52 (5.17) SPQ Delusion-like ideation 11.00 (5.03) 8.84 (3.85) 1.60 (2.20) 2.20 (2.22) SPQ Interpersonal 13.92 (7.49) 11.20 (5.10) 4.96 (4.35) 3.36 (2.87) SPQ Disorganization 7.48 (3.69) 6.96 (2.37) 1.56 (1.58) 1.96 (1.95) Total PDI-21 ‘Yes’ 9.48* (3.78) 6.68 (3.67) 2.72 (2.44) 3.50 (3.92) PDI-21 Distress 24.22* (15.41) 15.36 (10.55) 5.44 (5.39) 7.46 (11.77) PDI-21 Preoccupation 26.17* (14.83) 17.24 (11.63) 5.72 (6.27) 8.46 (11.77) PDI-21 Conviction 30.30* (15.16) 21.76 (13.71) 8.04 (7.85) 10.50 (12.06) MC-SDS 14.24 (4.50) 16.12 (4.90) 17.04 (6.54) 19.60 (4.96) Fatiguea (pre-experiment) 34.48 (16.70) 40.00 (16.60) 28.72 (13.92) 22.00 (13.99) Fatiguea (post-experiment) 47.56 (20.99) 37.71 (17.89) 37.40* (23.22) 23.00 (16.60) % of accepted ESRs (Session 1) 28.90 (18.92) 30.77 (21.29) 20.19 (17.44) 21.38 (21.67) Note. AP-Placebo, antipsychotic-placebo; SPQ, Schizotypal Personality Questionnaire; PDI-21, The 21-Item Peters et al. Delusions Inventory; MC-SDS, The Marlowe-Crowne Social Desirability Scale; a Fatigue score calculated using the percent of maximum possible score (POMP) (Cohen et al., 1999) p < .05, **p < .01

The median split procedure was implemented to subdivide the AP-Placebo and the no pill treatment groups into high and low schizotypy subsamples using their SPQ Total score. The AP- Placebo group and the no pill group did not significantly differ in terms of sex, age, or the level of education attained, neither among those with high schizotypy nor among those with low schizotypy (Table 15). An interesting observation was that among participants with high schizotypy, those from the AP-Placebo group had a significantly higher SPQ Total score (t(48) =

75 2.11, p = .04, r2 = .12). Similarly, those participants had a higher PDI-21 Total ‘Yes’ score (t(46) = 2.60, p = .01, r2 = .13), as well as the score for all three PDI-21 clusters: distress (t(46) = 2.34, p = .02, r2 = .11), preoccupation (t(46) = 2.33, p = .02, r2 = .11), and conviction (t(46) = 2.05, p < .05, r2 = .08). These differences were not observed among participants with low schizotypy. Results from our expectations survey replicated that pattern which suggests that inviting participants from the general population to take antipsychotic medications in the experimental setting presumably attracts people with higher schizotypy and delusion proneness. No difference, however, was observed in the percentages of accepted ESRs at session 1 in neither schizotypy subsample.

All subjects presented themselves with moderate levels of social desirability, with no significant differences observed. Baseline fatigue scores also did not differ between the two treatment groups, neither among high schizotypy subjects nor among low schizotypy subjects. Both high and low schizotypy participants who took the AP-Placebo had a higher post- experimental fatigue score than those from the no pill group, although a significant difference was observed only for those with low schizotypy (t(48) = 2.52, p = .015, r2 = .12). For the change in energy throughout the experiment, Treatment Group x Schizotypy interaction was non-significant.

Percentages of accepted social roles

Regardless of the treatment group, across the two sessions of the task participants with high schizotypy accepted a greater percentage of SRs than participants with low schizotypy for all four subcategories: ordinary favourable (High schizotypy, M = 62.85%, SE = 2.70%; Low schizotypy, M = 59.76%, SE = 2.70%), ordinary unfavourable (High schizotypy, M = 37.44%, SE = 2.43%; Low schizotypy, M = 32.63%, SE = 2.43%), extraordinary favourable (High schizotypy, M = 34.28%, SE = 3.15%; Low schizotypy, M = 28.15%, SE = 3.15%), extraordinary unfavourable (High schizotypy, M = 18.23%, SE = 1.90%; Low schizotypy, M = 12.10%, SE = 1.90%). However, no significant main effect of schizotypy was observed.

76

80 70 60 Ordinary favourable 50

40 Ordinary 30 Extraordinary unfavourable favourable 20 Extraordinary unfavourable % of accepted social roles 10 0 High Low High Low schizotypy schizotypy schizotypy schizotypy

Figure 15. Schizotypy x Treatment Group interaction for the percentages of accepted social roles across the two sessions of the social role acceptance task. The interaction was non-significant neither for extraordinary SRs nor for ordinary SRs. Error bars display the standard error of the mean. * p < .05, ** p < .01, *** p < .001, **** p < .0001.

Mixed-model repeated-measures ANOVA did not reveal a statistically significant Schizotypy x Treatment Group interaction (Figure 15). Nevertheless, participants with high schizotypy who took the AP-Placebo accepted a marginally smaller percentage of SRs than no pill participants with high schizotypy. The opposite was observed among those with low schizotypy: the AP- Placebo group accepted a slightly bigger percentage of SRs than the no pill group. Task session did not moderate the acceptance of SRs for high and low schizotypy participants as no significant interactions were detected.

Reaction Times (RTs)

Omnibus mixed-model repeated-measures ANOVA with schizotypy as the second between- subjects factor did not reveal any significant main effect of schizotypy. Nonetheless, regardless of the treatment group, those with high schizotypy were by 46.20 ms (SE = 20.26 ms) faster at accepting SRs relative to those with low schizotypy. This trend was seen for all four SR categories. For SR rejections, high schizotypy participants were by 25.92 ms (SE = 23.64 ms) faster than low

77 SR Acceptances SR Rejections AP-Placebo No Pill

Ordinary Ordinary 1100 1100

1050 1050

1000 1000

950 950

900 900 Reaction Time (ms) Reaction Time (ms) 850 850

800 800 High schizotypy Low schizotypy High schizotypy Low schizotypy

Extraordinary Extraordinary 1100 1100

1050 1050

1000 1000

950 950

900 900 Reaction Time (ms) Reaction Time (ms) 850 850

800 800 High schizotypy Low schizotypy High schizotypy Low schizotypy

Figure 16. Effect of the antipsychotic-placebo and Decision x Treatment group x Schizotypy group interaction effect on the mean reaction times (RTs) for ordinary and extraordinary social roles across the two sessions of the social role acceptance task. The interaction was non-significant neither for extraordinary SRs nor for ordinary SRs. Treatment group x Schizotypy interaction trend was observed, regardless of decision. Error bars represent the standard error of the mean. * p < .05, ** p < .01, *** p < .001, **** p < .0001.

78 schizotypy participants at rejecting OSRs but were by 6.39 ms (SE = 23.40 ms) slower at rejecting ESRs. Thus, for the rejection responses, a significant Extraordinariness x Schizotypy interaction 2 was observed (F(1, 96) = 4.95, p = .03, ηp = .05). Additionally, we found a significant Session x

2 Extraordinariness x Favourability x Schizotypy interaction (F(1, 96) = 4.47, p = .04, ηp = .04) which was also specific to rejection responses across the two sessions of the task. Post-hoc analyses, however, did not validate any significant Extraordinariness x Favourability x Schizotypy interaction neither in session 1 nor in session 2.

Furthermore, we did not find any moderation of the placebo effect by participants’ schizotypy as no statistically significant interactions were observed. However, the interaction trend was nevertheless detected. In participants with high schizotypy, those who took the AP-Placebo were generally faster at responding to SRs relative to those in the no pill group (AP-Placebo, M = 938.99 ms, SE = 28.72; No Pill, M = 985.23 ms, SE = 28.72). In contrast, in participants with low schizotypy, the AP-Placebo group was slower at responding to SRs than the no pill group (AP- Placebo, M = 1010.34 ms, SE = 28.72; No Pill, M = 962.84 ms, SE = 28.72) (Figure 16). This relationship between schizotypy and the treatmeng group was similar for accepted and rejected SRs.

N400 amplitude

The grand average event-related potentials for high and low schizotypy participants are shown in Figures 19a and 19b. As mentioned previously, to account for a prolonged N400 latency displayed by some participants, the mean voltage values were extracted from the 300-700 ms time window for the prefrontal (Fp1/2), frontal (F7/8, F3/4, Fz), frontocentral (Fc3/4, Fcz) and frontotemporal (Ft7/8) sites, and from the 300-500 ms time window for the rest of the scalp. Taking into consideration participants' schizotypy profile, in brief, we observed an overall reduction of the N400 amplitude at centroparietal and parietal sites in both schizotypy subgroups who took the AP-Placebo (Figure 17). This effect was greater among those with high schizotypy. At the prefrontal sites (Fp1/2), we saw a differential effect of placebo on the N400: while those with high schizotypy displayed a smaller N400 amplitude, those with low schizotypy showed a bigger and a more prolonged N400. Statistical analysis, however, did not validate any significant Treatment x Schizotypy interaction at Fp1/2. All things considered, the placebo effect was distributed across

79 the scalp for participants with high schizotypy but appeared more localized to centroparietal and parietal sites for participants with low schizotypy.

Across the two sessions of the task, the mixed-model repeated measures ANOVA rendered a significant main effect of schizotypy for all three electrode subsets: sagittal (F(1, 96) = 4.81, p = 2 2 .03, ηp = .05), parasagittal (F(1, 96) = 5.35, p = .02, ηp = .05), and lateral (F(1, 96) = 8.25, p = 2 .005, ηp = .08) (Table 16). All interactions with the session factor were non-significant. Regardless of the treatment group, all high schizotypy subjects showed a significantly smaller N400 amplitude than all low schizotypy subjects. Moreover, the absence of any interactions with the electrode or the hemiscalp factors testifies a relatively uniform distribution of this phenomenon across the scalp. At the sagittal subset, the main effect of schizotypy was seen at Cz and Pz, although the adjustment for multiple comparisons yielded this effect non-significant at these electrode sites. The main effect of schizotypy was significant at C3, Cp3/4, and P3/4 of the parasagittal subset as well as at T4 and Tp7/8 of the lateral subset (Table 17). As such, prefrontal, frontal and occipital electrodes were the only sites where no remarkable effect of schizotypy was seen. Despite no observed interactions with the treatment group, we nevertheless performed the in-depth post-hoc analyses for each electrode subset to identify significant differences between high and low schizotypy participants in their response to the AP-Placebo.

At the Pz electrode of the sagittal subset, both schizotypy subgroups exhibited a smaller N400 in response to placebo (Table 18). No moderation effect of schizotypy was seen at this site. Regarding the parasagittal subset, we saw that among subjects with high schizotypy, the AP- Placebo group showed a significantly smaller N400 amplitude than the no pill group at C3/4, Cp3/4, and P3/4. Those with low schizotypy showed a significant reduction in the N400 at Cp3 only – the electrode that neighbours the sagittal Pz. At the other electrodes of this subset, only a marginal decrease in N400 was seen. A similar moderating effect of schizotypy was observed at the Ft8 and T4 electrodes of the lateral subset, with high but not low schizotypy participants displaying a significantly reduced N400 amplitude upon taking the AP-Placebo.

80 Table 16 Summary of effects of schizotypy on the N400 amplitude 2 Electrode subset Within-subjects factor F df p ηp Sagittal Schizotypy 4.81 1, 96 .03 .05 Schizotypy x Treatment Group 0.25 1, 96 .62 .003 Schizotypy x Electrode 0.43 1.62, 155.55 .61 .004 Schizotypy x Electrode x Treatment Group 0.33 1.62, 155.55 .67 .003 Schizotypy x Session 2.96 1, 96 .08 .03 Schizotypy x Session x Treatment Group 1.82 1, 96 .18 .02 Schizotypy x Session x Electrode 0.50 1.71, 164.32 .58 .005 Parasagittal Schizotypy 5.35 1, 96 .02 .05 Schizotypy x Treatment Group 1.43 1, 96 .24 .02 Schizotypy x Electrode 1.61 1.90, 181.93 .20 .02 Schizotypy x Electrode x Treatment Group 1.86 1.90, 181.93 .16 .02 Schizotypy x Hemiscalp 0.06 1, 96 .81 .001 Schizotypy x Hemiscalp x Treatment Group 0.31 1, 96 .58 .003 Schizotypy x Session 1.82 1, 96 .18 .02 Schizotypy x Session x Treatment Group 1.68 1, 96 .20 .02 Schizotypy x Session x Electrode 0.06 1.66, 159.23 .92 .001 Schizotypy x Session x Hemiscalp 0.05 1, 96 .83 < .001 Schizotypy x Electrode x Hemiscalp 1.32 3.33, 319.96 .27 .01 Schizotypy x Electrode x Hemiscalp x 0.28 3.33, 319.96 .86 .003 Treatment Group Lateral Schizotypy 8.25 1, 96 .005 .08 Schizotypy x Treatment Group 2.02 1, 96 .16 .02 Schizotypy x Electrode 0.56 1.26, 121.32 .50 .006 Schizotypy x Electrode x Treatment Group 0.36 1.26, 121.32 .60 .004 Schizotypy x Hemiscalp 0.05 1, 96 .82 .001 Schizotypy x Hemiscalp x Treatment Group 0.15 1, 96 .70 .002 Schizotypy x Session 0.18 1, 96 .68 .002 Schizotypy x Session x Treatment Group 0.26 1, 96 .61 .003 Schizotypy x Session x Electrode 0.07 1.46, 139.91 .88 .001 Schizotypy x Session x Hemiscalp 0.71 1, 96 .40 .007 Schizotypy x Electrode x Hemiscalp 1.83 1.72, 165.11 .17 .02 Schizotypy x Electrode x Hemiscalp x 0.60 1.72, 165.11 .53 .006 Treatment Group

81 High schizotypy Low schizotypy

µV µV

Figure 17. Interpolated scalp map of the antipsychotic-placebo effect on the N400 amplitude in participants with high and low schizotypy across the two sessions of the social role acceptance task. Values denote mean voltage difference between the AP-Placebo and the no pill groups in the N400 time window. The effect of placebo was more profound in high schizotypy participants than in low schizotypy participants.

Table 17 Electrodes with significant main effect of schizotypy on the N400 amplitude Subset Electrode Statistical test

2 Parasagittal C3 F (1, 96) = 7.69, p = .007, FDR-p = .03, ηp = .07

2 Cp4 F (1, 96) = 7.56, p = .007, FDR-p = .03, ηp = .07

2 Cp3 F (1, 96) = 13.39, p = .0004, FDR-p = .01, ηp = .12

2 P4 F (1, 96) = 8.17, p = .005, FDR-p = .03, ηp = .08

2 P3 F (1, 96) = 9.96, p = .002, FDR-p = .03, ηp = .09

2 Lateral T4 F (1, 96) = 6.45, p = .01, FDR-p = .04, ηp = .06

2 Tp8 F (1, 96) = 8.05, p = .006, FDR-p = .03, ηp = .08

2 Tp7 F (1, 96) = 7.58, p = .007, FDR-p = .03, ηp = .07

Note. α = .05

82 Table 18 Electrodes with significant main effect of the antipsychotic-placebo on the N400 amplitude in participants with high versus low schizotypy Subset Electrode High schizotypy, df (1, 48) Low schizotypy, df (1, 48)

2 2 Sagittal Pz F = 9.73, p = .003, FDR-p = .03, ηp = .17 F = 10.37, p = .002, FDR-p = .03, ηp = .18

2 2 Parasagittal C4 F = 8.30, p = .006, FDR-p = .03, ηp = .15 F = 3.25, p = .08, FDR-p = .16, ηp = .06

2 2 C3 F = 9.44, p = .003, FDR-p = .03, ηp = .16 F = 5.62, p = .02, FDR-p = .06, ηp = .10

2 2 Cp4 F = 13.09, p = .0007, FDR-p = .02, ηp = .21 F = 5.80, p = .02, FDR-p = .06, ηp = .11

2 2 Cp3 F = 10.41, p = .002, FDR-p = .03, ηp = .18 F = 7.98, p = .007, FDR-p = .03, ηp = .14

2 2 P4 F = 12.70, p = .0008, FDR-p = .02, ηp = .21 F = 5.77, p = .02, FDR-p = .06, ηp = .11

2 2 P3 F = 8.01, p = .007, FDR-p = .03, ηp = .14 F = 6.95, p = .01, FDR-p = .05, ηp = .13

2 2 Lateral Ft8 F = 11.61, p = .001, FDR-p = .02, ηp = .19 F = 1.10, p = .30, FDR-p = .40, ηp = .02

2 2 T4 F = 8.33, p = .006, FDR-p = .03, ηp = .15 F = 1.55, p = .22, FDR-p = .33, ηp = .03

Note. Bold values denote statistical significance after the FDR correction, α = .05

83 LPP amplitude

The effect of the AP-Placebo on the LPP amplitude for high and low schizotypy participants is shown in Figures 18, 19a, and 19b. All things considered, placebo induced a local amplification of the LPP amplitude among high schizotypy participants that was seen primarily at the prefrontal and the frontotemporal sites of the right hemiscalp. In contrast, among those with low schizotypy, the effect was more generalized across the posterior hemiscalp, with the greatest differences seen at temporal, temporoparietal, and parietooccipital sites of the right hemiscalp. At the prefrontal sites (Fp1/2), high schizotypy subjects showed a bigger LPP in response to placebo, while the opposite was seen among those with low schizotypy. Notwithstanding the above, no significant Schizotypy x Treatment Group interaction was confirmed at these electrode sites.

For the statistical analysis, the mean voltages values corresponding to LPP were extracted from the 800-1200 ms time window for the prefrontal (Fp1/2), frontal (F7/8, F3/4, Fz), frontocentral (Fc3/4, Fcz) and frontotemporal (Ft7/8) sites, and from the 600-1200 ms time window for the rest of the scalp. The mixed-model ANOVA revealed no significant main effect of schizotypy nor any interactions with the treatment group (Table 19). Similarly, no interactions with the session factor were observed. Nevertheless, it’s worth mentioning that at all three electrode subsets, we saw that high schizotypy participants displayed a slightly bigger LPP than participants with low schizotypy, regardless of the treatment group they were assigned to.

Despite no significant interactions seen with the treatment group factor, we still performed additional in-depth analyses at each electrode site to identify the differences between high and low schizotypy subjects in their response to placebo. At session 2, among participants with high SPQ, a marginally bigger LPP was seen in the AP-Placebo group than in the no pill group at Ft8, T4, Tp8, and T6 of the right hemiscalp. Among participants with low SPQ, this effect was observed at C4, Cp4, T4, and Tp8 of the right hemiscalp as well as at Cp3, T3, Tp7, T5, and O1 of the left hemiscalp. After performing the correction for multiple comparisons, the effect of the treatment group was non-significant at the abovementioned electrode sites for both schizotypy subgroups.

84 Table 19 Summary of the effects of schizotypy on the LPP amplitude 2 Electrode subset Within-subjects factor F df p ηp Sagittal Schizotypy 0.28 1, 96 .60 .003 Schizotypy x Treatment Group 0.91 1, 96 .34 .009 Schizotypy x Electrode 1.34 1.25, 120.13 .26 .01 Schizotypy x Electrode x Treatment Group 0.33 1.25, 120.13 .62 .003 Schizotypy x Session 0.09 1, 96 .76 .001 Schizotypy x Session x Treatment Group 0.05 1, 96 .82 .001 Schizotypy x Session x Electrode 0.65 1.30, 124.95 .46 .007 Parasagittal Schizotypy 0.35 1, 96 .56 .004 Schizotypy x Treatment Group 0.08 1, 96 .76 .001 Schizotypy x Electrode 0.62 1.76, 168.56 .52 .006 Schizotypy x Electrode x Treatment Group 2.01 1.76, 168.56 .14 .02 Schizotypy x Hemiscalp 1.28 1, 96 .26 .01 Schizotypy x Hemiscalp x Treatment Group 0.10 1, 96 .76 .001 Schizotypy x Session 0.01 1, 96 .92 < .001 Schizotypy x Session x Treatment Group 0.05 1, 96 .82 .001 Schizotypy x Session x Electrode 0.85 1.74, 167.19 .42 .009 Schizotypy x Session x Hemiscalp 0.11 1, 96 .75 .001 Schizotypy x Electrode x Hemiscalp 0.43 2.41, 231.66 .69 .004 Schizotypy x Electrode x Hemiscalp x 0.18 2.41, 231.66 .87 .002 Treatment Group Lateral Schizotypy 0.60 1, 96 .44 .006 Schizotypy x Treatment Group 0.37 1, 96 .55 .004 Schizotypy x Electrode 0.62 1.33, 127.68 .48 .006 Schizotypy x Electrode x Treatment Group 0.71 1.33, 127.68 .44 .007 Schizotypy x Hemiscalp 1.56 1, 96 .21 .02 Schizotypy x Hemiscalp x Treatment Group 0.75 1, 96 .39 .008 Schizotypy x Session 0.02 1, 96 .88 < .001 Schizotypy x Session x Treatment Group 0.33 1, 96 .57 .003 Schizotypy x Session x Electrode 0.24 1.38, 132.88 .70 .002 Schizotypy x Session x Hemiscalp 0.28 1, 96 .60 .003 Schizotypy x Electrode x Hemiscalp 0.89 1.35, 129.58 .38 .009 Schizotypy x Electrode x Hemiscalp x 0.52 1.35, 129.58 .53 .005 Treatment Group

85 High schizotypy Low schizotypy Session 1

µV µV

Session 2

µV µV

Figure 18. Interpolated scalp map of the antipsychotic-placebo effect on the LPP amplitude in participants with high and low schizotypy at Session 1 (top) and Session 2 (bottom) of the social role acceptance task. Values denote mean voltage difference between the AP-Placebo and the no pill groups in the LPP time window. A notable effect of session was observed, with the increase in LPP amplitude seen by session 2 in both high and low schizotypy subgroups. The effect of placebo was localized anteriorly in participants with high schizotypy and posteriorly in participants with low schizotypy.

86 High schizotypy AP-Placebo No Pill

Low schizotypy

Figure 19a. Effect of the antipsychotic-placebo on event-related potentials for participants with high (top) and low (bottom) schizotypy at Session 1 of the social role acceptance task.

87 High schizotypy AP-Placebo No Pill

Low schizotypy

Figure 19b. Effect of the antipsychotic-placebo on event-related potentials for participants with high (top) and low (bottom) schizotypy at Session 2 of the social role acceptance task.

88 Conclusion

This study instantiates the effect of placebo expectations in the context of decision-making processes encountered in everyday life – social role playing. Conforming to the spreading- activation theory and the cognitive nature of mental imagery engendered by placebo expectations, we provided the electrophysiological evidence that non-specific expectations of the antipsychotic intake interfere with the basic semantic processing mechanisms of linguistic and action-related concepts, namely the spread of automatic activations and the inhibition of distant representations. This effect was further moderated by two correlates of delusion proneness – the inherent tendency to play extraordinary social roles and schizotypy. While these two constructs appear comparatively related, as evidenced by the replicated positive correlation between the percentages of accepted ESRs and the SPQ Total scores, a differential moderation effect on behavioural (percentages of accepted SRs and RTs) and electrophysiological (N400 amplitude and LPP topography) parameters was observed on account of the placebo response. The results of the study indicate that antipsychotic-placebo expectations conduced a nocebo response in participants with high delusion proneness, and ameliorative placebo response in participants with low delusion proneness. Controlling for this effect in future cognitive task paradigms involving the administration of antipsychotics will allow the researchers to account for a fraction of the neurochemical effect of the medication.

89 General Discussion

Synthesis of results and comparison to hypotheses

The general aim of this thesis was to investigate how expectations associated with the antipsychotic intake influence participants’ drive to play social roles as a factor of delusion proneness. After exploring the previously documented association between the tendency to play ESRs and schizotypy (Fernandez-Cruz et al., 2016), we aimed to examine similarities and differences between these two constructs in the context of the placebo/nocebo response. To this end, the thesis has presented two experiments: the ad hoc Experiment 1, which had a primary purpose of assessing the efficacy of placebo expectation intervention and exploring the attitudes towards antipsychotics along the schizotypy continuum; and applied Experiment 2 that uses a novel ecologically valid social role acceptance task to directly examine the effect of expectations on neuropsychological endophenotypes and biological markers of semantic processing. These two experiments are prerequisite steps to further scrutinize the effect of atypical antipsychotics risperidone and olanzapine on social role playing. Findings presented in this thesis can thus be harnessed to further isolate the neurochemical effect of those medications from the non-specific effects associated with antipsychotic-placebo expectations.

The first specific aim of this thesis was to quantify the tendency to play ESRs in the non- clinical population by means of the social role acceptance paradigm to see whether it could predict schizotypy and its respective dimensions: delusion-like ideation, interpersonal, and disorganization. This finding has been previously documented by Fernandez-Cruz et al. (2016) and the primary purpose of our analysis was to replicate this association on a smaller sample of healthy participants. It was hypothesized that individuals with a higher percentage of accepted ESRs would again have a higher SPQ total score alongside higher scores for three SPQ clusters. In line with this hypothesis, the study was successful at reproducing that association pattern: the percentage of accepted extraordinary unfavourable SRs – that is, the roles that differ the most from ordinary favourable SRs – had the best predictive power for both the SPQ and the PDI-21 scores. This again corroborates the view that personal drives to play social roles that exceed human physical or mental capabilities and that are viewed as disadvantageous by most people might engender subclinical delusion-like ideation and disorganized thoughts and behaviours.

90 While Fernandez-Cruz et al. (2016) reported the strongest association with the disorganized dimension of the SPQ, the present study showed that accepted extraordinary unfavourable SRs most strongly predicted the delusion-like thinking, which was further validated by a significant association with the PDI-21 scores. The PDI-21 is selectively designed to operationalize delusional ideation and the current study revealed that the percentage of accepted SRs had a better predictive power for the PDI-21 scores than for the SPQ scores. Incidentally, the weakest association with accepted SRs was observed for the interpersonal dimension of the SPQ, where significance was confirmed only for accepted SRs of extraordinary unfavourable type.

This raises a possible concern that the heterogeneous presentation of schizotypy and the unified operationalization of three different dimensions under a single construct might obscure certain relevant associations that could expound the etiology of constitutive symptom-like patterns of cognition and behaviour. Two prospective solutions can be proposed. The first one recommends establishing research study groups proceeding from specific dimensions of schizotypy instead of all dimensions combined. The selection of the quantifiable dimension would largely depend upon the association of interest aimed to be explored. The second solution emboldens the shift from a psychometrics-based approach towards an endophenotype-based approach (Insel & Culbreth, 2009; Insel et al., 2010), which has been auspiciously implemented in this study. Here, we propose a novel neuropsychological endophenotype of schizotypy, the tendency to play ESRs, that has the potential to incentivize a more objective quantification of what schizotypy represents on the cognitive and behavioural level.

However, it is worth noting that we observed a gradient-like relationship between the accepted percentages and the SPQ scores across the four role categories, meaning that ordinary favourable SRs were the ones accepted the most frequently, followed by ordinary unfavourable, extraordinary favourable, and, lastly, extraordinary unfavourable. Additionally, participants with higher SPQ scores accepted more social roles in general than those with lower SPQ scores, regardless of the role category. This finding provides substantial evidence in favour of the disorganization-like disturbances seen along the schizotypy continuum, as the drive to play ordinary roles would ultimately conflict with the drive to play extraordinary roles if the latter is accepted more frequently in the population with high schizotypy than with low schizotypy. Such conflict could

91 be responsible for bizarre actions, thought disturbances, poor insight, and difficulties in abstract thinking (Hardy-Baylé, Sarfati, & Passerieux). Furthermore, it seems that the drive to play ordinary SRs has somewhat a protective effect against schizotypal traits. A parallel with the putative link between creativity and psychosis proneness can be drawn, which, in our case, would translate into a smaller percentage of ESRs accepted by the low SPQ scorers (Fink, Benedek, Unterrainer, Papousek, & Weiss, 2014). All things considered, it is difficult to make a univocal conclusion specifying which one of the two schizotypy dimensions, delusion-like ideation or disorganization, is more likely to be better represented by the ESR acceptance phenotype. The multiple regression results presented in this work thus necessitate a further in-depth exploration of the association between the social role playing and other independent correlates accurately and reliably representing each dimension.

The second specific aim of this thesis was to establish whether placebo expectations, in general, influence participant’s performance in the social role acceptance paradigm. This was achieved in Experiment 2 by comparing the group that received a fully-deceptive antipsychotic- placebo to the group that received no pill. Before the start of the experiment, the AP-Placebo group was hypothesized to hold specific and non-specific expectations pertinent to the effect of antipsychotics, while the no pill group was hypothesized to hold none. Performing the global group-level behavioural analysis was thus our principle approach at meeting this specific aim.

We found no significant influence of placebo expectations on the percentages of accepted SRs: the expected gradient-like relationship for different SR categories was characteristic of both treatment groups, with ordinary favourable SRs accepted the most frequently, followed by ordinary unfavourable, extraordinary favourable, and extraordinary unfavourable. Correspondingly, placebo expectations exerted a negligible effect on the accompanying reaction times, where the AP-Placebo group was slightly faster at accepting unfavourable SRs at session 1. This effect, however, did not last until session 2 and thus most likely accounts for a brief change in attitudes subject to individual of certain SRs (Block & Funder, 1986). Taken together, the absence of significant behavioural differences mainly suggests that both treatment groups had equivalent cognitive schemas and baseline levels of personal drives to enact social roles. The alternative and a more plausible explanation, however, is that the effect of placebo

92 expectations was obscured by intra-group variability pursuant to individual differences and situational determination of the placebo response (Geers, Kosbab, Helfer, Weiland, & Wellman, 2007; Scott et al., 2007; Horing, Weimer, Muth, & Enck, 2014). This proposition further emphasizes the relevance of studying the effect of placebo expectations on social role playing within subsamples of participants predetermined as per their delusion proneness characteristics.

The third specific aim of this thesis was thus specifically designed to address this notion. In line with the previous reports that schizophrenia patients typically exhibit negative attitudes towards prescribed antipsychotics (Awad, 1993; Mizrahi et al., 2005; Gobjila et al., 2019), we conducted the online study with a goal to quantify placebo expectations along the schizotypy continuum. By presenting the information about common adverse effects as a form of the expectation intervention, we found that this information effectively ‘reshaped’ expectations in those with low schizotypy but was largely ineffective in those with high schizotypy. Specifically, after reading the paragraph from the consent form, participants with low schizotypy demonstrated a significant reduction in ratings of their expectancies regarding the effect of the antipsychotic on their cognitive abilities and executive function (i.e., concentration, distractibility, memory, multitasking ability, performance in everyday tasks, thought process), while participants with high schizotypy retained these expectations (Table 3a, 3b). With regard to expectancies about the antipsychotic affecting anxiety, creativity, energy, impulsivity, sexual function, and spontaneity, both groups showed a decrease in ratings, although the effect sizes were notably smaller for the high schizotypy group. As such, after reading the consent form, participants with low schizotypy had significantly lower expectations than participants with high schizotypy pertaining to the effect of the antipsychotic on concentration, reasoning ability, multitasking ability, performance in everyday tasks, impulsivity, and spontaneity, as illustrated by the between-group statistical comparisons (Table 2).

These findings are consistent with our hypothesis stemming from reports of the information processing deficits and abnormalities in mental imagery seen in individuals with high schizotypy (Aleman et al., 2005; Kiang & Kutas, 2005; Sack et al., 2005; Johnson et al., 2008; Wang et al., 2013; Mazhari et al., 2015). The information presented in the consent form explicitly stated the side effects that were likely to occur, which only encompassed disturbances in physical symptoms,

93 sleep, and energy levels (see Appendix B). After noting that antipsychotics were not supposed to exert its effect on cognitive and executive domains, individuals with low schizotypy were able to effectively utilize presented information to shape their specific expectancies about the effect of antipsychotics, mainly achieved by means of semantic mechanisms of mental imagery, such as retrieval and storage of mental representations (Pylyshyn, 1973; Kosslyn et al., 2006; Thomas, 2019). Those with high schizotypy, in contrast, had difficulty using this information to modify their beliefs, which, most likely, is attributed to self-referential thinking and cognitive hypermentalization associated with the positive dimension of schizotypy (Cicero & Kerns, 2011; Wastler & Lenzenweger, 2019, 2020). Given that referential thinking reflects the over- interpretation of stimuli as well as viewing external information as having specific meaning to the self, the corresponding deficits in self-relevant information processing in high schizotypy most likely explains why the expectations about the antipsychotic influencing the personal self in a negative way were retained (Lenzenweger, Bennett, & Lilenfeld, 1997). Moreover, schizotypy is associated with deficits in context processing – a component of working memory responsible for extracting pertinent information from the environment to select the appropriate response (Rinaldi, Lefebvre, Blekic, Laroi, & Laloyaux, 2018). The inability to efficiently use the context feasibly rendered high schizotypy participants incapable of integrating the presented information into a coherent whole, which otherwise would have facilitated the overall understanding of the meaning of the situation.

In line with these observations, we predicted that the presence of non-specific expectations would account for a differential effect of the antipsychotic-placebo in participants with high versus low delusions proneness in the social role acceptance paradigm. Specifically, we hypothesized that participants with low delusion proneness would commence the task holding only specific expectations about the side effects of antipsychotics that were presented in the informed consent form. Consistent with the cognitive-emotional model of the placebo effect proposed by Lundh (1987), placebo expectations lead individuals to pay selective attention to the physical signs of change, which are taken as evidence that placebo works. This is a so-called state of somatic focus – a mode of selective attention that guides the interpretation of expectancy-congruent somatic information and which thus have cognitive underpinnings (Cioffi, 1991; Brown, 2004; Geers et al., 2006). Somatic focus has been previously reported to moderate the relationship between

94 placebo expectancies and placebo response and could thus serve a paramount role in information processing and regulating future actions (Geers et al., 2006; Geers, Wellman, Fowler, Rasinski, & Helfer, 2011). As such, the cognitive boost attributed to somatic focus was hypothesized to induce the ameliorative placebo response in those with low schizotypy, which would get manifested through an increased drive to play social roles. The increase in the computational demands of the semantic network was consequently expected to cause a delay in reaction times among low schizotypy subjects.

Participants with high delusion proneness, on the other hand, were expected to commence the task while holding non-specific expectations about the effect placebo – that is, the effect of the medication on cognitive abilities and executive function that are not associated with the common side effects described in the consent form. Such negative expectations arising from referential thinking and deficits in context processing were hypothesized to induce a nocebo response, with an accompanying decrease in the drive to play social roles. Additionally, from the semantic perspective, those expectations were theorized to interfere with the activation of linguistic and action-related representations corresponding to presented social roles, thereby facilitating the recruitment of simplified cognitive strategies manifesting itself through more spontaneous responses with faster reaction times.

The results of the present study revealed that the tendency to play ESRs was a significant moderator of the placebo effect on the drive to play social roles. Relative to the no pill group, all HA-ESR participants who took the AP-Placebo accepted a smaller percentage of SRs, while all LA-ESR participants accepted a greater percentage of SRs. A similar trend in SR playing was observed for high and low schizotypy subgroups, although no significant interaction was confirmed. As such, expectations associated with the AP-Placebo intake decreased the drive to play social roles in subjects with high delusion proneness (i.e., a nocebo response) but increased this drive in those with low delusion proneness (i.e., an ameliorative placebo response). Furthermore, the interaction between placebo expectations and the tendency to play ESRs was more profound for SRs of extraordinary rather than ordinary type, which further corroborates the association between delusion proneness and ESR playing.

95 Personal drives to play social roles are fundamentally linked to motivation and reward seeking, with role models proposed to effectively set goal-directed activities of role aspirants, reinforce their existing goals, and facilitate the adoption of new goals (Morgenroth, Ryan, & Peters, 2015). From the neurobiological perspective, the mesolimbic dopaminergic transmission plays a vital role in the regulation of motivational and hedonic processes (Koob, 1996; Wise, 2004). While several molecular imaging studies have reported the increase in endogenous levels of mesolimbic dopamine that was directly proportional to the placebo response (de la Fuente-Fernández et al., 2001, 2002; Lindstone et al., 2010), a study by Scott et al. (2008) revealed the placebo versus nocebo response, in fact, exerts the opposite effect on the DA system. According to these authors, high placebo responses are associated with a greater DA release in the nucleus accumbens, while nocebo responses – with the deactivation of DA release. Anatomically and functionally, the nucleus accumbens communicates with the prefrontal cortex, with both regions forming a motivational salience network (Del Arco & Mora, 2008; Mannella, Gurney, & Baldassarre, 2013). This connectivity might be inherently linked to the state of frontocortical hypodopaminergia theorized to partly contribute to the manifestation of the cognitive symptoms of schizotypy and schizophrenia. From that standpoint, the increase in the drive to play SRs that this study reports for subjects with low delusion proneness might be attributed to the placebo-induced increase in endogenous DA levels that would reinforce motivation to engage in multiple social roles. In high delusion proneness subjects, where the decreased drive to play SRs was observed, the nocebo response might be linked to the state of hypodopaminergia exacerbated by the placebo, which not only diminishes the motivation to play social roles but also reinforces the manifestation of cognitive deficits ascribed to the disorganized dimension of schizotypy.

Similarly, conforming to our hypothesis, we report a significant interaction between the tendency to play ESRs and the placebo/nocebo response associated with the reaction times that accompanied the acceptance and rejection responses. It is worth noting, however, that decision, was an important mediator of this relationship. In comparison to participants from the no pill group, HA-ESRs who took the AP-Placebo were slower at accepting SRs but faster at rejecting them, while exactly the opposite was seen for LA-ESRs who took the AP-Placebo – they were faster at accepting SRs but slower at rejecting them. In contrast, by performing similar analyses for high and low schizotypy subgroups, we did not observe any interaction with decision: high

96 schizotypy participants who took the placebo were generally faster at both accepting and rejecting SRs, while low schizotypy participants were generally slower. In their study, Fernandez-Cruz et al. (2016) report that high schizotypy tends to be associated with slower RTs for both accepted and rejected social roles, while their analysis of the correlate of schizotypy, the tendency to play ESRs, revealed that HA-ESRs had faster RTs for accepted SRs but slower RTs for rejected SRs. The authors proposed that participants with a high tendency to play ESRs have a higher baseline level of activation of corresponding action-related representations.

This proposition can be further extended to the placebo/nocebo response and the differential effect exerted by these two correlates of delusion proneness. Our study showed that the AP- Placebo induced the nocebo response in those with high schizotypy and the placebo response in those with low schizotypy regardless of whether a ‘Yes’ or a ‘No’ response was provided. For high schizotypy subjects, interference of negative expectations with semantic processing of social roles makes certain representations harder to activate, which subsequently leads to a smaller number of representations to integrate with the context, resulting in simplified processing and faster RTs (Debruille et al., 2013). Moreover, this finding generally reflects impulsivity tendencies and reduced cognitive inhibition characteristic of high schizotypy (Peters, Pickering, & Hemsley, 1994; Rim, 1994). For low schizotypy subjects, somatic focus and increased attention lead to a greater number of representations activated, which increases the computational load of the semantic network and manifests itself in slower RTs (Maxfield, 1997). With reference to the tendency to play ESRs, this mechanism was observed only for rejected social roles – the ones participants were not willing to actively engage with. For accepted SRs, it appears that the higher baseline level of activation of representations corresponding to SRs aligned with the personal drives to enact those roles in real life serve a protective function against the nocebo effect in subjects with a higher tendency to play ESRs, thus preventing non-specific expectations from compromising the activity of the semantic network. In other words, a particularly strong drive to play those roles outperforms the interference effect of negative expectations. This observation confirms the idea that schizotypy and the tendency to play ESRs are related but at the same time distinct constructs, which prompts further investigation of how these correlates differ mechanistically on the behavioural level.

97 The fourth and final specific aim of this thesis was to examine the effect of the antipsychotic- placebo on the electrophysiological markers of semantic processing – the N400 ERP component indexing unconscious implicit memory processes, and the LPP component indexing conscious explicit memory processes. For the centropariental N400, we were expecting to see a decrease of the N400 amplitude in the AP-Placebo group due to interference of negative expectations with the automatic activation of semantic representations attributed to linguistic features and the core meaning of social roles. The present study has successfully shown this, with a maximal reduction in the N400 detected at the Pz electrode site (Figure 7). We also found that delusion proneness was a significant moderator of the placebo effect on the centroparietal N400: both high schizotypy and HA-ESR participants of the AP-Placebo group showed a bigger reduction in its amplitude than low schizotypy and LA-ESR participants, respectively. Moreover, those with high delusion proneness showed a generalized decrease in the N400 across the scalp, with the involvement of frontocentral and temporal areas (Figures 12 and 17). In contrast, among individuals with low delusion proneness, the N400 decrease was negligible and had a focal topographical distribution, primarily localized over the centroparietal electrode sites.

In line with the spreading-activation theory of Collins and Loftus (1975) and the idea of Kutas and Hillyard (1984) that the N400 indexes semantic activation, our results confirmed that placebo expectations interfere with the spread of automatic activations within the semantic network. This means that when the fundamental information about a social role is extracted, an overall smaller number of representations would get activated and would need to undergo further processing – selection of appropriate representations (i.e., the ones closely related to the core meaning of the social role) and inhibition of inappropriate representations (i.e., the ones distantly related or unrelated to the core meaning of the social role) (Debruille, 1998; Debruille, 2007; de Loye, Beaucousin, Bohec, Blanchet, & Kostova, 2013). From the semantic inhibition perspective, a smaller N400 would directly index a smaller amount of inhibition following a semantic spread, leading to the overall enhanced experience of noise incoming from disinhibited inappropriate representations. As such, among individuals with high delusion proneness, negative expectations about the effect of the antipsychotic would trigger an electrophysiological nocebo response manifesting itself in the limited spread of automatic activations and insufficient semantic

98 inhibition, which would further contribute to the destabilized semantic network, the augmentation of one's focus on irrelevant stimuli and the underlying disorganization.

Additionally, our study revealed a moderation effect of delusion proneness on the frontal N400, where the antipsychotic-placebo decreased its amplitude in high delusion proneness subjects but increased it in low delusions proneness subjects. This interaction was significant for the tendency to play ESRs but not for schizotypy, which further supports the idea that these two constructs are related but at the same time distinct – in this instance, on the electrophysiological level. Semantic network within the frontal lobes hosts mental representations of perceptions, actions, and emotions, which, according to the theories of embodied and grounded cognition, form a coding mechanism for the meaning of social role stimuli (Ellis & Tucker, 2000; Barsalou, 2008; Borghi & Cimatti, 2010). Consequently, a placebo-induced reduction in the N400 observed in high delusion proneness participants would index a limited activation of action-related representations and insufficient semantic inhibition of distant representations. Because of the overall smaller number of representations to process, the cognitive system will adopt a simplified strategy prompting a participant to make a decision on whether to play a social role or not with faster reaction time. The increase in the N400 that was seen in low delusion participants would reflect the opposite, followed by the adoption of complex cognitive strategies with a higher computational load and an accompanying slower reaction time for provided responses.

The modulation of the placebo effect by delusion proneness in relation to the frontal N400 supports the previously discussed association between the placebo/nocebo response and endogenous dopamine release. Dopamine regulates the E/I balance of the semantic network and increases the signal-to-noise ratio (SNR), thus ensuring proper separation of relevant from irrelevant representations (Winterer & Weinberger, 2004; Copland et al., 2009; Tonelli, 2014). Consistent with the findings of Scott et al. (2008), the nocebo response would induce the state of frontocortical hypodopaminergia in high delusion proneness individuals, which would disinhibit the network and lead to an enhanced experience of noise and subsequent recruitment of irrelevant action-related representations. In low schizotypy individuals, the placebo response would trigger the release of endogenous DA, resulting in sufficient semantic inhibition, decreased experience of noise, and the direction of cognitive resources towards processing relevant representations.

99 Moreover, the baseline DA levels in high versus low delusion proneness individuals before the AP-Placebo intake could also in part account for the differential effect of the antipsychotic-placebo on the cascade of semantic processing events, although this warrants further empirical investigation.

Concerning the LPP component, a significant effect of session was seen, where the AP- Placebo induced a focal amplification of the LPP amplitude over the right temporoparietal sites at session 1 but a more diffuse increase in the LPP effect at session 2, with a maxima again detected over the right temporoparietal sites (Figure 8). The placebo-induced augmentation of the LPP is consistent with the inhibition hypothesis of the N400, where smaller N400 should be followed by larger LPPs (Dolchin & Coles, 1988; Sergent et al., 2005; Sinha et al., in press). Smaller inhibition of representations during early processing would ultimately lead to the placement of a larger amount of information into the working memory, where such information would have to be adequately integrated with its contents (Petten et al., 1991). Considering that our samples were comprised of healthy individuals, the increase in the LPP amplitude might also reflect a higher cognitive load placed on the semantic system during high-order processing in order to redeem the interference effect of placebo expectations on early processing. As the observed increase in the LPP was session-dependent, it appears that placebo expectations do not augment the LPP amplitude directly but rather target earlier stages of semantic processing followed by an indirect compensatory mechanism at the later stages. Most likely, such a mechanism is utilized by the cognitive system to sustain adequate levels of decision evaluation, attention, and performance. In our task, all participants who took the AP-Placebo became significantly more tired from session 1 to session 2, which suggests that their working memory demanded more attentional resources. Since no effect of session was seen for the behavioural variables and the N400, the amplification and the topographical spread of the in LPP effect at session 2 could thus reflect the adaptive mechanism through which the cognitive system sustains adequate integration of activated representations with the contents of the working memory.

Contrary to our hypothesis, delusion proneness did not significantly moderate the LPP amplitude at a specific region of interest but rather predetermined contrasting topographical distribution of the LPP effect. In particular, upon taking the AP-Placebo, high delusion proneness

100 participants displayed a more positive LPP component over the anterior hemiscalp, while low delusions proneness participants – over the posterior hemiscalp (Figures 13 and 18). Although the exact functional significance of late frontal versus later posterior positivities is yet to be elucidated, two possible explanations can be proposed. The dedifferentiation hypothesis views the anterior LPP shift as the decline in neural efficiency attributed to deficits in frontal lobe functioning (Dickinson, Ragland, Calkins, Gold, & Gur, 2006; Davis & Jerger, 2014; Knowles et al., 2014). While participants with low delusion proneness integrate social role representations employing either working or long-term memory, which are more posterior processes, those with high delusions proneness continue utilizing hypofunctional frontal lobe strategies. Ultimately, this causes a breakdown in executive function when attentional demands exceed the available attentional resources, hence shifting the neural activity anteriorly. Another theory, the compensation hypothesis, posits that frontal lobes are recruited to rectify global deficits in cognitive function (Mahurin, Velligan, & Miller, 1998; Ragland, Yoon, Minzenberg, & Carter, 2007). With relevance to individuals with high delusion proneness, this process would help them maintain task performance at the optimal level by changing their core strategy of processing social role representations. The current study revealed no significant main effect of schizotypy on the percentages of accepted SRs or the accompanying RTs, which suggests that both schizotypy subgroups maintained adequate levels of task performance. Integrating the EEG/ERP technique with spatial imaging modalities can provide a more comprehensive insight into the role of frontal lobes in high-order processing of self-relevant stimuli among delusion-prone individuals.

Limitations and Challenges

Several limitations and challenges for the current set of experiments are important to be acknowledged. First and foremost, it is crucial to highlight the inferential nature of Experiment 1 as the effect of the expectation intervention and the effect of the antipsychotic-placebo on social role acceptance were tested on distinct samples, although with identical demographic and psychometric characteristics. In itself, Experiment 1 was exploratory in nature and was designed specifically to test the hypothesis giving foundation for the effect of the expectation intervention, which further endorsed the mechanistic explanation why participants with high and low delusion proneness responded to the antipsychotic-placebo in a different fashion. To compensate for this limitation, samples from both experiments were exposed to exactly the same informed consent

101 form, which grounds preliminary implications for the generalizability of the observed effect. Replication, however, is necessary and a future study where expectations of the effect of antipsychotics would be assessed in the directly tested sample is warranted.

Secondly, our results and interpretations in Experiment 2 are limited to the between-subjects study design and the recruitment bias. Due to ethical considerations, different advertisement strategies for participants in the AP-Placebo and the no pill groups had to be employed, where the advertisement for the AP-Placebo group explicitly stated that participants would be coming to the laboratory to take the antipsychotic medication. This possibly resulted in the attraction of high sensation seekers, which was reflected in significantly higher total SPQ scores in high schizotypy participants who took the AP-Placebo, although no significant difference between the two treatment groups was seen within the HA-ESR subgroup. To compensate for this limitation, we aimed to assess placebo expectations in the sample identical in their demographic and psychometric characteristics to the AP-Placebo group tested in Experiment 2, and asked participants to indicate whether they would be willing to participate in the follow-up study that would involve the administration of antipsychotic medications. In sum, utilizing the same recruitment strategies for both treatment groups, implementing random assignment and creating a double-blinded trial could possibly overcome observer-expectancy and subject-expectancy effects that should be taken into account when interpreting the results presented in this work.

Another challenge arises from the use of healthy participants in both experiments and the inherent heterogeneity of the schizotypy construct, with associated difficulties in obtaining psychometric measures accurately representing this construct. While recruiting participants from the general population allows circumventing secondary effects characteristic of schizophrenia spectrum disorders, such as positive symptoms, disease chronicity, and previous antipsychotic exposure, the true effect of placebo expectations might have been obscured if only a subpopulation recruited in each study had psychometric and neurobiological aberrations congruent with the underlying mechanism proposed. With the construct of schizotypy in the current study representing the combination of delusion-like ideation, interpersonal, and disorganization constituents, amalgamating these dimensions to define schizotypy might have hindered the true association between delusion proneness and the effect of placebo expectations on social role

102 acceptance. Here, we proposed a novel neuropsychologically-based endophenotype (i.e., the tendency to play ESRs) that has a potential to overcome some of the challenges associated with the validity of schizotypy operationalization by means of psychometrics. Nonetheless, examining the moderation effect of each dimension of schizotypy independently might provide further insight into the etiology of behavioural and neurobiological aberrations associated with the placebo/nocebo response.

A final challenge may be pertinent to all EEG/ERP based studies and concerns the inherent heterogeneity of ERPs themselves. The proposition of the ERP-based biomarkers is largely based on group-level differences – in other words, the between-group comparison of mean voltage within a certain time window of interest. Even within the same paradigm, however, ERPs across participants are highly divergent, which can be reflected in the presence or absence of certain components, the relativity of local maxima and minima (e.g., the absolute value of the N400 peak can be a positive voltage), and variability in the peak latency for certain components. While personal drives to play social roles are shaped through purely individualistic exposure to the behaviour of others, the group-level ERP biomarkers proposed in the present study may or may not be translatable to individual information processing cognitive strategies and their association with delusion proneness. With training on a large set of metrics in a multivariate predictive model, machine learning algorithms have a better potential to achieve more powerful individual-level classification, although the cost-effectiveness of this technique is a major source of concern.

Future Directions

The long-term goals of this work encompass a thorough investigation of the effect of atypical antipsychotics olanzapine and risperidone on the drive to play social roles, with a prospect of translating the social role acceptance paradigm to the clinical setting. ERP biomarkers have a potential to serve as treatment response predictors for delusion-like and disorganization-based symptomatology in schizophrenia spectrum disorders and other disorders with psychotic features. The next logical step would thus be to apply the social role acceptance paradigm to the clinical population. In the end, the task can be used as a one-day test to assign suitable pharmacological intervention based on its immediate observable effect on the number of accepted ESRs, the reaction times, and the proposed EEG biomarkers of semantic processing.

103 EEG artifacts, such as eye blinks and myograms, prevented us from obtaining reliable ERP measures that would index the acceptance and rejections of social roles for each of the four categories separately. As such, in the present study we were unable to investigate whether delusion proneness moderates the effect of placebo expectations on the ERP amplitudes as a function of decision as well as of role extraordinariness and favourability ratings. Therefore, the short-term goal of the future studies would be to modify its paradigm by introducing more trials or changing the ITI of the sequence since such findings could provide further insight into the association between the tendency to play ESRs and the electrophysiological indexes of semantic processing.

The response expectancy theory formed a theoretical foundation for the hypotheses of the present study, with observed placebo/nocebo response interpreted as a bottom-up readout of bodily signs of change or the absence of thereof. With the advent of a novel Bayesian ‘predictive processing’ approach to perception, placebo effects can be viewed as top-down inferences constantly generated by the brain and subsequently revised upon the encounter of bottom-up interoceptive changes (Ongaro & Kaptchuk, 2019). Various external cues aid the brain at interpreting interoceptive changes in the body as a direct consequence of placebo intake, including experimental paraphernalia, emotional and cognitive engagement with the researcher, perception of the EEG procedure, as well as tablet characteristics (e.g., shape, colour) (Kaptchuk & Miller, 2015). Future studies should thus take a more integrative approach to the factors contributing to the shaping of expectations surrounding the effect of antipsychotics and explore how the direct manipulation of psychosocial cues and experimental setting parameters modulates the placebo/nocebo response.

Finally, solving the inverse problem is a major challenge for EEG/ERP-based studies as the underlying source of neural activity is affected by numerous factors including but not limited to technical or biological EEG noise, as well as source-modelling and head-modelling errors (Grech et al., 2008). Similarly, the EEG signals themselves are subject to distortion due to the current passing through several layers of biological tissue (i.e., cerebrospinal fluid, meninges, skull, blood vessels, scalp) before being properly captured by the EEG system (Gu, Mohamed Ali, L’Abbée Lacas, & Debruille, 2014). As such, the underlying neural sources and the topography distribution of ERPs presented in this work prompt further validation with other neuroimaging techniques with

104 better spatial resolution (e.g., fMRI). Although those techniques have their own limitations, combining the evidence from several neuroimaging modalities will provide prerequisite evidence upholding neurobiological strata of the social role acceptance and the interplay between delusion proneness and placebo/nocebo response.

Final conclusion and contribution to original knowledge

We were successful at replicating the results of Fernandez-Cruz et al. (2016) by demonstrating that participants who were willing to engage in a greater number of ESRs had a higher total SPQ score. This further corroborates the notion that the drive to play ESRs is an independent factor predicting disorganization seen along the schizotypy continuum. With extraordinary unfavourable SRs having the strongest positive correlation with the total SPQ scores, schizotypal traits are most likely linked to an individual’s tendency to play roles that are considered disadvantageous. With this finding being consistent across two studies, we further split our participants into high and low acceptors of extraordinary social roles and discussed similarities and differences between two constructs characterizing delusion proneness – the tendency to play extraordinary social roles and schizotypy.

Additionally, we were able to demonstrate the efficacy of the placebo expectation intervention technique through the experimental presentation of the information about the negative side effects of antipsychotics. It was revealed that before the start of the experiment, participants with high schizotypy had non-specific expectations about the effect of the medication on certain domains of cognition, while low schizotypy participants had almost none. Such a difference in pre-existing attitudes towards antipsychotics seen along the schizotypy continuum most likely accounted for the differential response to the antipsychotic-placebo that was observed behaviourally and electrophysiologically. In participants with high delusion proneness, a nocebo response was observed, as evidenced by the decreased drive to play social roles and the use of simplified cognitive strategies to extract and process the meaning of presented social roles. In participants with low delusion proneness, in contrast, ameliorative placebo response was seen, reflected by the enhanced drive to play social roles and the recruitment of complex cognitive strategies with a higher computational load. The observed modulation of the N400 amplitude

105 prompts the mechanistic explanation of the sequence of semantic processes that might be influenced by mental representations underlying placebo expectations.

This work proposes a potential explanation of how social roles can be viewed as semantic constructs as well as how cognitive processing of such constructs can be compromised along the schizotypy continuum. Consistent with the social learning theory proposed by Bandura (1977), our findings highlight the importance of social role playing in the etiology and maintenance of certain schizotypal traits such as delusion-like ideation and disorganization. Clinically, checking the drive to accept ESRs can be used as a diagnostic and assessment tool for schizotypal characteristics, as well as a general follow-up strategy in the process. The unique design of this experiment also has the potential to be used as a one-day test that can be applied by clinicians to determine the best pharmacotherapy treatment option for schizophrenia patients.

Additionally, our study provides unique contributions that strengthen the theory of placebo. We were able to successfully demonstrate that one’s attitudes and expectations can have a significant impact on indexes of semantic processing. This expectation effect should be controlled in the future randomized controlled trials aiming at establishing the efficacy of antipsychotic medications as well as in future experiments using cognitive task performance as a candidate endophenotype of delusion proneness. By detecting real changes in neuronal activity, our findings also contribute to the research upholding the neurobiological basis of placebo response. Although a more in-depth investigation of the influence of psychosocial cues and the experimental setting is warranted, we successfully identified electrophysiological correlates of specific suggestions and particular research context. Considering the highly heterogeneous and condition-specific nature of placebo effects, the work presented in this thesis offers grounds for neuroimaging studies to further investigate brain and network mechanisms that could underlie expectation effects.

106 References

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130 APPENDIX A

Experiment 1: Verbatim of the follow-up study advertisement used for screening

But first, we have to ask you whether you would participate in a follow-up study that will be evaluating the effect of antipsychotic medications. As such, a low dose of an antipsychotic (risperidone or olanzapine) will be given to you. In addition, an electrode cap will be placed on your head to record the brain’s electrical activity (EEG) while you perform simple tasks on a computer. This follow-up brain study is separate from the current survey so keep in mind that you might not be offered to participate in it. This study would take place at the Douglas Hospital in Verdun and would last approximately 3-4 hours. You would be compensated $13 per hour and you could expect to receive at least $45 (+ a full reimbursement of travel expenses).

o Yes o No

Note. All participants had to answer ‘Yes’ in order to proceed further with the survey completion.

131 APPENDIX B

Experiment 1: Verbatim of the consent form paragraph presented as part of the expectation intervention

Assume you are participating in a study where you are given a single dose of antipsychotic medication olanzapine. Consider the following information:

It is known that antipsychotic medications function to improve a number of psychotic symptoms. The exact mechanisms of the function remain incompletely understood. One possibility is that these medications facilitate, directly or indirectly, the mechanisms that allow us to understand unexpected information. By doing so, these medications could help patients with inaccurate beliefs (e.g., delusions) to change their minds.

Olanzapine is a drug that is widely used in clinical practice by thousands of patients and is approved by the Food and Drug Administration. The 2.5 milligram dose you will be taking is almost the lowest dose that is given to adults. There are several possible side effects associated with this medication, although it is extremely unlikely that they could occur at the dose involved in this study. Also, note that all studies that examined side effects looked at repeated administration of the drug, rather than at a single dose.

The adverse effects that you might experience are sleepiness and drowsiness, dry mouth, light- headedness, constipation, increased appetite, stomach upset (nausea / indigestion), restlessness, sense of muscle weakness (with no actual loss of strength), insomnia, and muscle stiffness. However, mild drowsiness is the only adverse effect that is likely to occur.

132 APPENDIX C

Experiment 1: Expectations Assessment Scale (EAS)

Effect presence subscale. Please use the following scale to indicate whether you think an antipsychotic would affect certain aspects of your thinking and personality to a large extent or not at all. When answering this question, please think about whether an antipsychotic would have an effect or not.

0 – Not at all; 1 – To a small extent; 2 – To some extent; 3 – To a moderate extent; 4 – To a great extent; 5 – To a very great extent;

0 1 2 3 4 5 Cognitive functions (attention, memory, visual perception, ○ ○ ○ ○ ○ ○ information processing and reasoning) Memory ○ ○ ○ ○ ○ ○ Concentration ○ ○ ○ ○ ○ ○ Distractibility ○ ○ ○ ○ ○ ○ Reasoning ability ○ ○ ○ ○ ○ ○ Multitasking ability ○ ○ ○ ○ ○ ○ Performance in everyday tasks (e.g., driving, remembering ○ ○ ○ ○ ○ ○ important days, managing finances, etc.) Thought process ○ ○ ○ ○ ○ ○ Levels of energy ○ ○ ○ ○ ○ ○ Anxiety ○ ○ ○ ○ ○ ○ Impulsivity ○ ○ ○ ○ ○ ○ Spontaneity ○ ○ ○ ○ ○ ○

133 Creativity ○ ○ ○ ○ ○ ○ Perception of pain ○ ○ ○ ○ ○ ○ Feeling of nausea ○ ○ ○ ○ ○ ○ Sleepiness ○ ○ ○ ○ ○ ○ Movement and motion ○ ○ ○ ○ ○ ○ Appetite ○ ○ ○ ○ ○ ○ Sexual function ○ ○ ○ ○ ○ ○ Note. Items adapted from Rabipour et al. (2018): Cognitive functions, Memory, Concentration, Distractibility, Reasoning ability, Multitasking ability, Performance in everyday tasks.

Effect valence subscale. Please use the following scale to indicate whether you think an antipsychotic would affect certain aspects of your thinking and personality very positively or very negatively. When answering this question, please think about what kind of effect an antipsychotic would have.

1 – Very negatively (score -3); 2 – Fairly negatively (score -2); 3 – Somewhat negatively (score -1); 4 – I have absolutely no expectations (score 0); 5 – Somewhat positively (score 1); 6 – Fairly positively (score 2); 7 – Very positively (score 3);

1 2 3 4 5 6 7 Cognitive functions (attention, memory, visual ○ ○ ○ ○ ○ ○ ○ perception, information processing and reasoning) Memory ○ ○ ○ ○ ○ ○ ○ Concentration ○ ○ ○ ○ ○ ○ ○ Distractibility ○ ○ ○ ○ ○ ○ ○ Reasoning ability ○ ○ ○ ○ ○ ○ ○

134 Multitasking ability ○ ○ ○ ○ ○ ○ ○ Performance in everyday tasks (e.g., driving, ○ ○ ○ ○ ○ ○ ○ remembering important days, managing finances, etc.) Thought process ○ ○ ○ ○ ○ ○ ○ Appetite ○ ○ ○ ○ ○ ○ ○ Sexual function ○ ○ ○ ○ ○ ○ ○ Note. Items adapted from Rabipour et al. (2018): Cognitive functions, Memory, Concentration, Distractibility, Reasoning ability, Multitasking ability, Performance in everyday tasks.

Effect direction subscale. A single minimal dose of an antipsychotic would make me

1 – Significantly less (score -3); 2 – Much less (score -2); 3 – Somewhat less (score -1); 4 – I have absolutely no expectations (score 0); 5 – Somewhat more (score 1); 6 – Much more (score 2); 7 – Significantly more (score 3);

1 2 3 4 5 6 7 Tired ○ ○ ○ ○ ○ ○ ○ Anxious ○ ○ ○ ○ ○ ○ ○ Impulsive ○ ○ ○ ○ ○ ○ ○ Spontaneous ○ ○ ○ ○ ○ ○ ○ Creative ○ ○ ○ ○ ○ ○ ○ Able to feel pain ○ ○ ○ ○ ○ ○ ○ Nauseous ○ ○ ○ ○ ○ ○ ○ Sleepy ○ ○ ○ ○ ○ ○ ○ Agitated ○ ○ ○ ○ ○ ○ ○

135

Effect strength subscale. Please use the following scale to indicate to what extent you think an antipsychotic would make you feel

0 – Not at all; 1 – To a small extent; 2 – To some extent; 3 – To a moderate extent; 4 – To a great extent; 5 – To a very great extent;

0 1 2 3 4 5 Sad ○ ○ ○ ○ ○ ○ Joyful ○ ○ ○ ○ ○ ○ Emotionally blunted ○ ○ ○ ○ ○ ○ Excited ○ ○ ○ ○ ○ ○ Weird ○ ○ ○ ○ ○ ○ Defenceless ○ ○ ○ ○ ○ ○ Confused ○ ○ ○ ○ ○ ○ Psychotic (having difficulties determining what is real and ○ ○ ○ ○ ○ ○ what is not, having false beliefs, seeing or hearing things that others do not see or hear)

136 APPENDIX D

Experiment 2: Social roles and their characteristics

This thesis acknowledges the use of the open access social role stimuli bank from the following source:

Fernandez-Cruz, A. L., Ali, O. M., Asare, G., Whyte, M. S., Walpola, I., Segal, J., & Debruille, J. B. (2016). Embrained drives to perform extraordinary social roles predict schizotypal traits in the general population. npj Schizophrenia, 2(1).

137 APPENDIX E

Experiment 2: Electrode placement and ERP characteristics

Figure F1. Extended 10-20 system with 28 channels (American Electroencephalographic Society, 1991). Ground electrode positioned 2 cm anterior to Fz. Linked ears (A1/A2) used as the reference. Electrodes grouped into three subsets: sagittal (Fz, Fcz, Cz, Pz), parasagittal (Fp1/2, F3/4, Fc3/4, C3/4, Cp3/4, P3/4, O1/2), and lateral (F7/8, Ft7/8, T3/4, Tp7/8, T5/6).

Table F1 Trials included in the ERP computation post artifact rejection AP-Placebo No Pill M (SD) M (SD) Session 1 Figure 9 Total 119.92 (42.67) 127.68 (41.61) Figure 14a HA-ESR 121.84 (41.09) 113.24 (42.72) Figure 14a LA-ESR 118.00 (44.98) 142.12 (35.72) Figure 19a High schizotypy 120.80 (36.38) 121.68 (43.63) Figure 19a Low schizotypy 119.04 (48.92) 133.68 (39.46) Session 2 Figure 9 Total 113.90 (50.88) 130.88 (41.79) Figure 14b HA-ESR 110.68 (47.14) 116.48 (44.38) Figure 14b LA-ESR 117.12 (55.14) 145.28 (34.13) Figure 19b High schizotypy 107.20 (42.93) 128.80 (43.11) Figure 19b Low schizotypy 120.60 (57.86) 132.96 (41.21) Note. AP-Placebo, antipsychotic-placebo; HA-ESR, high acceptors of extraordinary social roles; LA-ESR, low acceptors of extraordinary social roles.

138 Table F2 Electrode channel interpolation formulae Electrode channel Interpolation formula Fp2 Fp2 = Fp1 Fp1 Fp1 = Fp2 F7 F7 = (2*Fp1 + Ft7) / 3 F8 F8 = (2*Fp2 + Ft8) / 3 Fz Fz = (Fcz + 0.5*F3 + 0.5*F4) / 2 Cz Cz = (2*Fcz + Pz) / 3 Pz Pz = (P3 + P4) / 2 P4 P4 = (Cp4 + 0.5*Pz + 0.5*T6) / 2 P3 P3 = (Cp3 + 0.5*Pz + 0.5*T5) / 2 T6 T6 = (2*O2 + Tp8) / 3 T5 T5 = (2*O1 + Tp7) / 3 T4 T4 = (Ft8 + Tp8) / 2 T3 T3 = (Ft7 + Tp7) / 2 F4 F4 = (Fc4 + 0.5*Fz + 0.5*F8) / 2 F3 F3 = (Fc3 + 0.5*Fz + 0.5*F7) / 2 Ft8 Ft8 = (F8 + T4) / 2 Ft7 Ft7 = (F7 + T3) / 2 Fc4 Fc4 = (0.5*Fcz + 0.5*Ft8 + F4 + C4) / 3 Fc3 Fc3 = (0.5*Fcz + 0.5*Ft7 + F3 + C3) / 3 Fcz Fcz = (0.5*Fc3 + 0.5*Fc4 + Fz + Cz) / 3 C4 C4 = (0.5*Cz + 0.5*T4 + Fc4 + Cp4) / 3 C3 C3 = (0.5*Cz + 0.5*T3 + Fc3 + Cp3) / 3 Tp8 Tp8 = (T4 + T6) / 2 Tp7 Fp7 = (T3 + T5) / 2 Cp4 Cp4 = (C4 + P4) / 2 Cp3 Cp3 = (C3 + P3) / 2 O2 O2 = O1 O1 O1 = O2

139 Table F3 Number of participants per interpolation formula Session 1 Session 2 AP-Placebo No Pill AP-Placebo No Pill (N = 50) (N = 50) (N = 50) (N = 50) Fp2 - 1 - - Fp1 2 4 4 4 F7 - - - - F8 - - 1 1 Fz - - - - Cz - 2 - 2 Pz - - - - P4 - 1 - 1 P3 - 1 - 1 T6 - 1 - - T5 - - - - T4 4 1 3 - T3 2 - 2 1 F4 - 1 1 - F3 - 1 1 - Ft8 - 1 1 1 Ft7 - 1 - 3 Fc4 1 1 - - Fc3 1 - 1 1 Fcz - - - - C4 - - 1 - C3 - - - - Tp8 1 - - - Tp7 - - 1 - Cp4 - - - - Cp3 - - 1 - O2 - - - - O1 - - - 1

140