Universiteit_Proefschrift

29-04-2008

11:29

Pagina 1

Mirjam Sprong | Adolescents at risk of psychosis

Adolescents at risk of psychosis

a comparison of the “At Risk Mental State” and Multiple Complex Developmental Disorder

Mirjam Sprong

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 2

Mirjam Sprong | Adolescents at risk of psychosis

The research presented in this thesis was supported by a grant from ZON-MW (ZorgOnderzoek Nederland/Netherlands Organization for Scientific Research), project 2630.0001. It was carried out at the Department of Child and Adolescent Psychiatry, University Medical Center Utrecht, the Netherlands. Sprong, Mirjam Adolescents at risk of psychosis: a comparison of the “At Risk Mental State” and Multiple Complex Developmental Disorder - Thesis Utrecht University ISBN: 978-90-393-4809-3 Copyright © 2008 Mirjam Sprong Alle rechten voorbehouden. Niets uit deze opgave mag worden verveelvoudigd, opgeslagen in een automatisch gegevensbestand, of openbaar worden gemaakt, in enige vorm of op enige wijze, hetzij elektronisch, mechanisch, door fotokopieën, opname op enigerlei manier, zonder voorafgaand schriftelijke toestemming van de auteur. All rights reserved. No part of this publication may be reproduced in any form by any electronic or mechanical means (including photocopy, recording, or information storage and retrieval) without the prior written permission of the author Cover design: Marieke Vromans Layout: DKGS Grafisch Servicebureau, www.dkgs.nl Printed in the Netherlands by PrintPartners Ipskamp

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 3

Mirjam Sprong | Adolescents at risk of psychosis

Adolescents at risk of psychosis a comparison of the “At Risk Mental State” and Multiple Complex Developmental Disorder

Adolescenten met een risico op psychose een vergelijking tussen de “At Risk Mental State” en Multiple Complex Developmental Disorder (met een samenvatting in het Nederlands)

Proefschrift ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de rector magnificus, prof. dr. J.C. Stoof, ingevolge het besluit van het college voor promoties in het openbaar te verdedigen op dinsdag 3 juni 2008 des ochtends te 10.30 uur door Mirjam Sprong geboren op 19 september 1975 te Rotenburg, Duitsland

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 4

Mirjam Sprong | Adolescents at risk of psychosis Promotoren:

Prof. dr. H. van Engeland Prof. dr. H. Swaab

Co-promotor:

Dr. P.F. Schothorst

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 5

Mirjam Sprong | Adolescents at risk of psychosis

Contents Chapter 1

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

Chapter 2

Pathways to psychosis: a comparison of the Pervasive Developmental Disorder subtype Multiple Complex Developmental Disorder and the “At Risk Mental State“ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

Chapter 3

Neurocognitive and behavioral vulnerability markers for psychosis in adolescents at high risk: a comparison of Multiple Complex Developmental Disorder and the “At Risk Mental State” . . . . . . . . . . . 65

Chapter 4

Facial affect processing in adolescents at high risk for psychosis . . . . . 91

Chapter 5

Theory of Mind in schizophrenia: a meta-analysis . . . . . . . . . . . . . . . 127 Correspondence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155

Chapter 6

Summary and general discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161

Appendix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173 Nederlandse samenvatting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183 Dankwoord. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195 Curriculum Vitae. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 6

Mirjam Sprong | Adolescents at risk of psychosis

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 7

Mirjam Sprong | Adolescents at risk of psychosis

Chapter 1

Introduction

Mirjam Sprong

Rudolf Magnus Institute of Neuroscience/Department of Child and Adolescent Psychiatry, University Medical Center Utrecht, the Netherlands

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 8

Mirjam Sprong | Adolescents at risk of psychosis

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 9

Mirjam Sprong | Adolescents at risk of psychosis

1. Introduction This chapter provides a theoretical background for the following chapters, which have been written as separate papers to be published in scientific journals. An overview of the literature will be given and some of the germane concepts of this dissertation will be explicated. In addition, the aims and design of the Dutch Prediction of Psychosis Study, which provided the framework for this dissertation, will be described. In the final section I will give a brief overview of the content of the following chapters.

2. Psychosis A psychosis is a severe disturbance of reality testing, which is evidenced by a lack of insight in the pathological nature of experienced hallucinations or delusions, or by cognitive and behavioral disorganization (Kaplan et al. 1994). According to the 4th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), psychoses are part of the syndromes of psychotic disorders such as schizophrenia and schizoaffective disorder, but they may also arise in other psychiatric disorders, in particular the affective disorders (American Psychiatric Association 1994). Schizophrenia is the most prevalent and most widely studied of the psychotic disorders. Its lifetime prevalence rate is estimated between 1 and 1.5%, and its 12-months incidence rate is estimated between 0.025 and 0.05% (Bijl et al. 2002; Kaplan et al. 1994). A large meta-analysis has shown that schizophrenia is diagnosed 1.4 times more often in men than in women (Aleman et al. 2003). Due to their relative rareness and classification differences between studies, epidemiological data for the other psychotic disorders are less clear. In the Netherlands Mental Health Survey and Incidence Study for example, the estimated prevalence rate of non-affective psychosis was 0.4%, and of affective psychosis 1.1% (Hanssen et al. 2003). In another large epidemiological study, the estimated 12-month incidence rate of all psychotic disorders combined was 0.035% (Kirkbride et al. 2006). A recent review of the literature showed that the median age of onset of non-affective psychotic disorder lies somewhere between the late teens through early 20s (Kessler et al. 2007). The rareness of psychotic disorders is offset by their severity. Schizophrenia in particular has been described as one of the most burdensome and costly illnesses worldwide. Life expectancy of individuals diagnosed with schizophrenia is reduced, mostly as a consequence of suicide. They have to be hospitalized repeatedly, suffer from considerable disabilities, and are often dependent on care and welfare services. Furthermore, the illness places a considerable burden on the friends and relatives who care for them (Rössler et al. 2005). Before proceeding, it is important to note that the classification of psychotic disorders

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 10

Mirjam Sprong | Adolescents at risk of psychosis remains a subject of considerable debate. Researchers disagree about whether psychiatric disorders in general should be classified using a dimensional or a categorical approach (Jablensky 2005a and 2005b; Mullen 2003; Widiger 2005). In addition, schizophrenia is considered to be a heterogeneous disorder in terms of clinical characteristics as well as etiology, and there is debate on whether or not the schizophrenia concept should be abandoned in favor of research targeted at particular symptoms such as psychosis (Costello 1992; Mojtabai and Rieder 1998). In this dissertation, we focus on the development of psychotic episodes - operationalized as the presence of positive symptoms with an instrument-defined psychotic intensity and a duration of more than one week (see section 7.2.1.) - rather than psychotic disorders.

3. Pathways to psychosis Psychoses are not exclusive to the psychotic and affective disorders. Other disorders that are associated with elevated risks of psychotic symptoms or schizophrenia-spectrum disorder include (subtypes of) the pervasive developmental disorders (e.g. Mouridsen et al. 2007; Stahlberg et al. 2004; Van Engeland and Van der Gaag 1994), Klinefelter syndrome (e.g. DeLisi et al. 1994 and 2005; Kumra et al. 1998b; Kunugi et al. 1999; Van Rijn et al. 2006), 22q11-deletion syndrome (e.g. Arinami 2006; Baker and Skuse 2005; Debbane et al. 2006; Murphy et al. 1999; Murphy and Owen 2001; Vorstman et al. 2006), and some of the DSM-IV personality disorders, in particular paranoid, schizoid, schizotypal, and borderline personality disorder (e.g. American Psychiatric Association 1994; Asarnow 2005; Benvenuti et al. 2005; Dowson et al. 2002; Rodriguez Solano and Gonzalez 2000). Furthermore, several researchers have argued that individuals with schizophrenia should be divided into two major subgroups based on the age of onset of first noticeable premorbid abnormalities (e.g. Fuller Torrey et al. 1994; Murray et al. 1992; Neumann et al. 1995; Offord and Cross 1969; Rossi et al. 2000). The first subgroup is described as having a markedly abnormal development from early childhood, with further escalation in adolescence or young adulthood. The second subgroup has a relatively normal development throughout childhood, followed by behavioral changes later in life. The observations that psychoses do no exclusively occur in the context of psychotic disorders, and that there are fundamental differences in the early development of individuals with schizophrenia, indicate that there are different developmental pathways to psychosis.

4. Vulnerability markers for psychosis For many years it has been acknowledged that some individuals with schizophrenia

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 11

Mirjam Sprong | Adolescents at risk of psychosis show behavioral abnormalities long before the onset of a first psychotic episode (e.g. Bleuler E. 1911; Bleuler M. 1978; Fuller Torrey et al. 1994; Offord and Cross 1969). This suggests that the pathological processes predisposing to schizophrenia may already be present early in life. Vulnerability-stress models postulate that these predispositional factors combine with environmental stressors to precipitate psychotic episodes, whereas internal and external protective factors reduce the likelihood of their development. More insight into these predisposing and protecting factors enhances the understanding of the pathogenesis of psychosis. Also, from a clinical perspective, it is essential for improving the identification of at-risk individuals, and for developing optimal early intervention strategies. Predispositional factors that are recognizable premorbidly are called vulnerability markers. These are studied using various research methods. Firstly, they are studied retrospectively or in a follow-back design in individuals with psychotic disorders. Secondly, they are studied prospectively in population-based cohort studies in which comparisons are made between those individuals who later develop psychotic symptoms or a psychotic disorder and those who do not. Thirdly, they are studied cross-sectionally as well as prospectively in various populations at elevated risk of developing a first psychotic episode. High-risk populations that have traditionally received the most research attention are individuals with a genetic risk for psychosis, i.e. offspring or siblings of individuals with schizophrenia or schizoaffective disorder, and individuals with schizotypal personality disorder or schizotypal traits. Well-established vulnerability markers for schizophrenia include delayed developmental milestones, abnormal language and motor development, social maladjustment, schizotypal personality traits, neurocognitive impairment, psychophysiological dysfunctions (e.g. abnormalities in smooth pursuit eye movements and event related potential amplitudes), and structural and functional brain abnormalities (Cornblatt and Obuchowski 1997; Davies et al. 1998; Diwadkar et al. 2004; Ellison et al. 1998; Erlenmeyer-Kimling 2000; Fuller Torrey et al. 1994; Fusar-Poli et al. 2007; Jones and Tarrant 2000; Keshavan et al. 2005; Kremen et al. 1994; Mäki et al. 2005; Niemi et al. 2003; Offord and Cross 1969; Olin and Mednick 1996; Sitskoorn et al. 2004; Snitz et al. 2006; Szoke et al. 2005; Trandafir et al. 2006; Whalley et al. 2005). Vulnerability markers for psychosis are almost invariably studied in the context of schizophrenia. However, the observation that there are different developmental pathways to psychosis suggests that there may be different pathogeneses that may be expressed premorbidly as different vulnerability markers. Comparing vulnerability markers in high-risk populations with different developmental backgrounds is of great interest, because it may not only lend more insight into the many different biological and environmental causes of psychosis, but also into the heterogeneity of the manifestation of the psychotic syndrome.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 12

Mirjam Sprong | Adolescents at risk of psychosis

5. At Risk Mental State The prodromal phase of psychotic illness is the premorbid phase that starts from the departure of the individual’s normal experience and behavior, and ends with the onset of an overt psychotic episode (McGorry et al. 2000). Retrospective studies have shown that the majority of individuals with schizophrenia experience such a prodromal phase. Its characteristics include a gradual decline in previous levels of functioning at school or work, social withdrawal, a lack of initiative and interests, peculiar behaviors, subtle changes in thoughts, emotions, and perceptions, and subclinical psychotic symptoms such as hallucinations and delusional ideas (e.g. Häfner et al. 1998 and 1999; Moller and Husby 2000; Schothorst et al. 2006; Yung and McGorry 1996). Jackson et al. (1995) showed that prodromal phases not only occur in schizophrenia, but are also common in other psychotic disorders. In the last decade, there has been an increasing research interest in the prodromal phase of schizophrenia. As Cornblatt et al. (2002) pointed out, this appears to have evolved from developments in two research traditions. Firstly, results from early-intervention research suggested that individuals with schizophrenia who had a longer duration of untreated psychosis had a poorer clinical and social outcome (reviewed by Marshall et al. 2005; Norman et al. 2005; Norman and Malla 2001). This first led to attempts to start treatment more quickly after psychosis-onset, and then to the idea that treatment before psychosis-onset would lead to an even better outcome. Secondly, genetic-risk research struggled with the need for long follow-up periods, and a lack of predictive power due to low transition rates. This led to a search for a high-risk group with a higher and more imminent risk of psychosis. Both research traditions turned their focus toward the prodromal phase, because individuals who have symptoms that suggest that they may in a prodromal phase were expected to be at “ultra-high risk” for progression to psychosis within a brief follow-up period (i.e. within ± 1 year). McGorry and his colleagues in Melbourne were the first to develop diagnostic criteria for the identification of these ultra-high risk individuals (reviewed by Phillips et al. 2002). They specified three diagnostic categories, i.e. having: (1) attenuated, i.e. subclinical, positive symptoms, (2) a brief psychotic episode that resolves spontaneously within one week, and (3) a combination of a genetic risk (i.e. having a close relative with a diagnosis of schizophrenia) and a substantial decline in general level of functioning within the past year. Individuals who met one or more of these criteria were thought to be at ultra-high risk for developing psychosis in the near future. Other terms that have been used to describe these individuals include “putatively prodromal”, “clinical high risk” or “at-risk mental state” (ARMS). For reasons of consistency, the latter term will be used predominantly

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 13

Mirjam Sprong | Adolescents at risk of psychosis throughout this dissertation. Following the Australian work, many research projects have been set up, sometimes with small variations on the specific diagnostic criteria for ARMS (reviewed by Bechdolf et al. 2006; Cornblatt et al. 2002; Olsen and Rosenbaum 2006b; Phillips et al. 2005; Yung 2007). The underlying aims of all of these studies are to enhance the understanding of the pathogenesis of schizophrenia and psychosis, and to improve the ability to predict who will develop psychosis in order to improve outcome by early intervention. Various instruments have been developed for the assessment of the ARMS criteria, with the most frequently used being the Comprehensive Assessment of At-Risk Mental States of the Melbourne group, and the Structured Interview for Prodromal Syndromes, which was developed by McGlashan and his colleagues at Yale university (reviewed by Addington 2004; Olsen and Rosenbaum 2006a). Early ARMS studies reported promisingly high transition rates of 28-46% within 6 months, and 35-54% within 12 months (e.g. Cannon et al. 2008; Miller et al. 2002; Yung et al. 2003 and 2004). However, more recent studies have found lower transition rates of for example 10% after 6 months (Yung et al. 2006), and 15% after 12 months (Haroun et al. 2006). It is not clear whether this reduction is explained by more effective treatment in the prodromal phase, or by the inclusion of more false positives due to more vigorous recruitment strategies (Yung et al. 2007). Gross (1997) describes another approach to studying prodromal risk which is based on the early works of Huber who introduced the concept of “basic symptoms”. These are described as subtle, subclinical, and often only self-perceivable disturbances of thought processes, perception, drive and affect. They are considered to be underlying the overt psychotic symptoms and the direct expression of the organic basis of psychosis, hence the term basic. Traditionally, basic symptoms have been assessed with the Bonn Scale for the Assessment of Basic Symptoms that was developed by Gross and colleagues (e.g. described in Gross 1997). Prospective studies have shown that some of the basic symptoms have a good predictive validity for developing schizophrenia after 8-10 years (Klosterkötter et al. 1997 and 2001). Hambrecht et al. (2002) used a combination of three DSM-III prodromal symptoms and six specific basic symptoms as an operationalization of “potentially prodromal”. Within 15 months 5 of 51 (9.8%) individuals with at least two of these symptoms made a transition to psychosis. In some of the more recent studies, the prodromal risk concept introduced by McGorry and colleagues is combined with the basic symptom prodromal risk concept, e.g. in the Cologne Early Recognition and Intervention project (FETZ; Pukrop et al. 2006 and 2007), the Bruderholz Early Psychosis Service (Simon et al. 2007), the Basel Early Recognition Study (Simon et al. 2005), the European Prediction of Psychosis Study (Klosterkötter et al. 2005; Nieman et al. 2007), and the present study. In some of the FETZ studies the

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 14

Mirjam Sprong | Adolescents at risk of psychosis prodromal phase is explicitly conceptualized as comprising two stages, an early and a late prodromal phase (e.g. Pukrop et al. 2006). The early prodromal phase is then operationalized as having one or more of the following: (1) a functional decline plus genetic risk, (2) a functional decline plus pre- or perinatal complications, and (3) basic symptoms. The late prodromal phase is then operationalized as having: (1) attenuated positive symptoms, and/or (2) transient psychotic symptoms.

6. Multiple Complex Developmental Disorder Pervasive Developmental Disorders (PDD) have frequently been associated with elevated risks of psychotic symptoms and schizophrenia (Clarke et al. 1989; Konstantareas and Hewitt 2001; Tantam 1988). Stahlberg et al. (2004), for example, showed that 9 of 129 (7%) adults with PDD diagnoses met diagnostic criteria for bipolar disorder with psychotic features, and 10 of 129 (7.8%) met diagnostic criteria for schizophrenia or another psychotic disorder. Recently, Mouridsen et al. (2007) reported that 31 of 89 (34.8%) adults with childhood-diagnoses of atypical autism were diagnosed with a schizophrenia spectrum disorder at least once in their life. Atypical autism is the 10th edition of the International Classification of Diseases and Related Health Problems (ICD-10) equivalent of the DSM-IV diagnosis PDD - Not Otherwise Specified (PDD-NOS). PDD-NOS is considered to lie on the continuum of PDDs which also includes Autistic Disorder, Rett’s Disorder, Childhood Disintegrative Disorder, and Asperger’s disorder (American Psychiatric Association 1994). Individuals with PDDNOS form a heterogeneous group with autistic-like symptoms of varying severity, including impairments in social interaction, communication and/or rigid and stereotyped behavior patterns, but they fail meet the full criteria for autistic disorder. In an attempt to remedy some of the heterogeneity of PDD-NOS, Cohen et al. (1986) distinguished a group of children with: (1) early-onset affect dysregulation and high levels of anxiety, (2) consistently impaired social behavior and sensitivity, and (3) impaired cognitive processing (i.e. thought disorder). In the past, various labels have been proposed for this combination of symptoms, including borderline syndrome of childhood, childhood schizophrenia, and childhood schizoid or schizotypal disorder (Ad-Dab'bagh and Greenfield 2001; Cohen et al. 1986; Wolff 1995). Cohen et al. proposed the term Multiplex Developmental Disorder (MDD), and developed a set of diagnostic criteria for the syndrome. In later publications they refined the diagnostic criteria, and changed the name to Multiple Complex

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 15

Mirjam Sprong | Adolescents at risk of psychosis Developmental Disorder (MCDD; Towbin et al. 1993). Further refinement of the diagnostic criteria for MCDD was proposed by Buitelaar & Van der Gaag (1998). The acceptance of MCDD as a discrete diagnostic category is not yet widespread, and the disorder is not yet included in the DSM-IV or ICD-10 classification systems. Cohen et al. (1986 and 1994) mentioned that M(C)DD belongs to the group of PDDs, or is at least related to it. However, it is not clear whether they believe that all MCDD cases should have a diagnosis of PDD(-NOS). Research showed that children with MCDD can be differentiated from children with autistic disorder (Van der Gaag et al. 1995) and PDDNOS (De Bruin et al. 2006) based on their clinical and behavioral characteristics. Cohen et al. (1986) also mentioned that the diagnostic boundaries between schizotypal disorder, childhood schizophrenia and MCDD are not clear, and suggested that some of the children with MCDD may later develop schizophrenia. A follow-up of 55 children with MCDD by Van Engeland & Van der Gaag (1994) has indeed revealed an elevated risk of schizophrenia-spectrum illness: 22% that were followed until adolescence and 64% that were followed into young-adulthood had developed schizophrenia-spectrum disorder. Further evidence for a possible connection between MCDD and schizophrenia comes from a study by Jansen et al. (2000) in which children with MCDD showed impaired cortisol responses to psychosocial stress (i.e. a public speaking task), similar to those that had earlier been found in individuals with schizophrenia (Jansen et al. 1998), whereas children with autistic disorder did not differ from healthy controls (Jansen et al. 2003). In a series of papers on childhood-onset schizophrenia by researchers of the National Institute of Mental Health, a group of children was described who did not meet the DSM-III-R criteria for schizophrenia (e.g. Jacobsen and Rapoport 1998; Kumra et al. 1998a). These children were characterized by: (1) a poor ability to distinguish fantasy from reality as evidenced by ideas of reference and brief perceptual disturbances, typically under stress or when falling asleep, (2) emotional lability disproportionate to precipitants (i.e. dramatic mood outbursts and periodic aggression), (3) impaired interpersonal skills despite desire to initiate social interactions with peers, and (4) absence of formal thought disorder They were provisionally labeled Multi-Dimensionally Impaired (MDI). The authors argued that the clinical features of MDI resemble those of MCDD, but that “[MDI children]… lack the severe impairments in social interaction, stereotyped behaviors and interests, inability to engage in make-believe play, characteristic profile of intellectual performance, and deviant language development commonly seen in pervasive developmental disorders” (Kumra et al. 1998a). Furthermore, because high rates of schizophrenia spectrum illness were found in the first-degree relatives of the MDI

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 16

Mirjam Sprong | Adolescents at risk of psychosis children, and because there were similarities between the brain morphologic abnormalities of the MDI children and the children with schizophrenia, the researchers concluded that MDI may be on the schizophrenia spectrum rather than the spectrum of PDDs. Confusingly, many of the children who did meet the diagnostic criteria for childhood-onset schizophrenia had PDD characteristics; it was reported that 34% demonstrated transient symptoms of PDD, such as hand flapping and echolalia during the premorbid period (Jacobsen and Rapoport 1998), and that 25% had a lifetime diagnosis of PDD (Sporn et al. 2004). Cross-center comparisons are necessary to establish the similarities and differences between MDI and MCDD, but the described characteristics are at the least suggestive of an overlap between the two diagnoses.

7. The Dutch Prediction of Psychosis Study The present dissertation forms part of a larger study called the Dutch Prediction of Psychosis Study (DUPS). DUPS is a cooperation between the Child and Adolescent Psychiatry Department of the University Medical Center (UMC) in Utrecht, and the Vroegtijdige Onderkenning Risico Symptomen [translated: Early Recognition of Risk Symptoms] program of the Psychiatric Clinic for Adolescents of the Academic Medical Center (AMC) in Amsterdam.

7.1. General aims of DUPS DUPS is a longitudinal, naturalistic field study, which focuses on early detection of individuals at high risk for psychosis. The general aims and design of the DUPS project have evolved from the AMC participation in the international European Prediction of Psychosis project (EPOS; Klosterkötter et al. 2005). Like EPOS, DUPS has four main research questions: 1.

Pathways to care: How do individuals at high risk for psychosis access their health care system? A systematic retrospective assessment of pathways to care and onset of symptoms, and an evaluation of delays and obstacles to adequate treatment will form an empirical database to design awareness and prevention programs for the community in order to reduce the duration of untreated illness.

2.

Prediction of psychosis: What should be assessed in order to predict transition to psychosis? The predictive validity of past and present symptoms and deficits, risk indicators, personality, neurocognitive and neurobiological measures, as well as their possible synergisms, will be evaluated.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 17

Mirjam Sprong | Adolescents at risk of psychosis 3.

Disabilities: When and how do social, educational, vocational and other functional impairments start in prodromal patients, and what is their course? The aim is to define the deficits and needs in the prodromal stages of the illness by using a systematic prospective assessment of disabilities and quality of life of individuals at high risk for psychosis.

4.

Early interventions: What kinds of interventions are applied in high-risk individuals, by whom, and what is their cost-effectiveness? Any intervention such as psychotherapy or medication and institutional/non-institutional support offered to individuals at high risk for psychosis in the participating regions is monitored and evaluated for its cost-effectiveness and benefits to the person. The aim is to assess possible applications and chances of success of early detection and intervention.

Both sites have additional research questions according to their specific interests. In the UMC we are mainly interested in comparisons of different populations at elevated risk of developing psychosis. The aims of the present dissertation were: 1.

to cross-sectionally compare potential vulnerability markers for psychosis in two groups of high-risk adolescents with different developmental pathways to psychosis

2.

to explore social cognitive impairments as potential vulnerability markers for psychosis

Because follow-up assessments are still ongoing, the predictive validity of these potential vulnerability markers for the transition to psychosis is not part of this dissertation.

7.2. Design and procedure of DUPS The design of DUPS involves comprehensive multi-level assessment and two-year followup of individuals who are at high risk of developing a first psychotic episode. In this section, the design and procedures of the DUPS project will be described in more detail, with an emphasis on the procedures at the UMC site.

7.2.1. Participants and recruitment The first high-risk group consisted of adolescents with an ARMS. This was operationalized as being help-seeking and meeting one or more of four research criteria that are assessed with the Structured Interview for Prodromal Syndromes (SIPS; McGlashan et al. 2001; Miller et al. 1999 and 2003) and the semi-structured Bonn Scale

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 18

Mirjam Sprong | Adolescents at risk of psychosis for the Assessment of Basic Symptoms-Prediction List (BSABS-P; Schultze-Lutter and Klosterkötter 2002; Vollmer-Larsen et al. 2007). Research criteria for At Risk Mental State (ARMS): 1. Attenuated Positive Symptoms, i.e. reporting at least one of the following symptoms assessed with SIPS P1-P5 and D1 (score 3-5): ideas of reference, odd beliefs or magical thinking, unusual perceptual experiences, odd thinking and speech, suspiciousness or paranoid ideation, odd behavior or appearance. Symptoms have to appear several times a week for a period of at least one week within the last three months. 2. Brief, Limited or Intermittent Psychotic Symptoms, i.e. reporting at least one of the following symptoms assessed with SIPS P1-P5 and D1 (score 6): ideas of reference, odd beliefs or magical thinking, unusual perceptual experiences, odd thinking and speech, suspiciousness or paranoid ideation, odd behavior or appearance with a psychotic intensity with a total duration of one week or less. 3. Familial Risk plus Reduced Functioning, i.e. having a schizotypal personality disorder or a first- or second degree relative with a psychotic disorder and a 30% reduction in level of social, occupational/school, and psychological functioning for at least one month in the past year. 4. Basic Symptoms, i.e. reporting two or more of a selection of nine basic symptoms of the ‘Cognitive thought disturbances’ scale. These symptoms have been present during the last three months (score ≥ 3). The complete lists of symptoms assessed by the SIPS and BSABS-P interviews are displayed in Tables 1 and 2.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 19

Mirjam Sprong | Adolescents at risk of psychosis

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 20

Mirjam Sprong | Adolescents at risk of psychosis

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 21

Mirjam Sprong | Adolescents at risk of psychosis

The main researchers at the UMC and the AMC were trained for assessment and scoring of the SIPS and the BSABS-P interviews by the original authors (T.J. Miller and F. SchultzeLutter). The interrater reliability at the UMC site was examined by calculating the intraclass correlation coefficient (rICC) for five BSABS-P and five SIPS interviews that were each independently rated by three researchers. The overall rICC value was 0.89 for the SIPS scale, 0.86 for the BSABS-P scale, and above 0.81 for all subscales (Table 3). All rICC values were thus excellent. Note that the rICC value for the BSABS-P scale Motor disturbance is not available, because very few participants reported this type of basic symptoms.

In the UMC a second high-risk group was included in order to compare vulnerability markers for psychosis in adolescents with different developmental pathways to psychosis. This group consists of adolescents with clinical diagnoses of PDD-NOS (American Psychiatric Association 1994; Table 4), who additionally met Cohen et al.’s diagnostic criteria for MCDD (Cohen et al. 1994; Table 5). MCDD diagnoses are confirmed by expert clinical opinion after psychiatric examination including the Autism Diagnostic Interview-Revised (Lord et al. 1994), and a parent-interview based on the MCDD criteria by Cohen et al. that was developed for internal use at the UMC.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 22

Mirjam Sprong | Adolescents at risk of psychosis

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 23

Mirjam Sprong | Adolescents at risk of psychosis

High-risk participants were excluded if they met one or more of the following exclusion criteria: Exclusion criteria for both high-risk groups: 1. UMC: 12 years > age > 18 years (AMC: 16 years > age > 28 years) 2. History of a psychotic episode > 1 week, defined as the presence of positive symptoms that are seriously disorganizing, i.e. a score of 6 on any of the items of the SIPS-Positive Symptoms subscale (P1-5), or on the SIPS-item ‘Odd behavior or appearance’ (D1) 3. Alcohol or drug abuse or the symptoms are suspected to be due to the effects of alcohol or drugs 4. History of known or suspected neurological trauma or an endocrinological disorder 5. Verbal IQ < 75 (part of neuropsychological testing) 6. No informed consent (for participants < 16 years, the parents or legal guardians had to co-sign) At the UMC, high-risk participants were recruited by distributing information about the DUPS project via oral presentations and brochures amongst health care providers in the region of Utrecht. In addition, intake reports were screened regularly by the researchers to minimize the number of missed eligible patients (i.e. patients who might meet the ARMS criteria or have an MCDD diagnosis). During the inclusion period of 36 months, 228 patients were referred to the UMC site because they were suspected to meet one or more of the ARMS criteria or to have MCDD. In those who were considered eligible by the researchers and gave informed consent, the fulfillment of the inclusion and exclusion criteria was examined with the use of screening questionnaires, (psychiatric) interviews with the patients and parents including the SIPS and the BSABS-P, and - if present - information in the medical records. The numbers of referred, screened and included patients are presented in Flow Chart 1. At the UMC, the first high-risk subject was included in June 2003. Therefore, with an inclusion period of 36 months and a follow-up period of 24 months, the anticipated end date of the data collection will be in June/July 2008.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 24

Mirjam Sprong | Adolescents at risk of psychosis

n=228 referred

n=30 did not meet intake criteria: n=10 no suspected ARMS symptoms or MCDD, n=10 outside age range, n=5 psychotic episode > 1 week, n=4 VIQ 1 week, n=1 symptoms caused by drugs, n=1 neurological disorder

n=81 included: n=49 ARMS, n=32 MCDD

Figure 1. Flow-chart of the screening and inclusion process at the UMC

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 25

Mirjam Sprong | Adolescents at risk of psychosis

At the UMC, a nonpsychiatric control (NPC) sample was recruited from secondary schools in the region of Utrecht, with permission of the school boards. They were excluded if they met one or more of the following exclusion criteria: Exclusion criteria for the nonpsychiatric control participants (NPC): 1. 12 years > age > 18 years 2. History of any known or suspected psychiatric illness in the NPC or in a first degree relative 3. History of a known or suspected psychotic illness in a second degree relative 4. Alcohol or drug abuse 5. History of known or suspected neurological trauma or endocrinological disorder 6. VIQ < 75 7. Meeting one or more of the ARMS criteria 8. No informed consent (for participants < 16 years, the parents or legal guardians had to co-sign) A total of 96 NPC participants were screened. Of those that were screened, 14 were excluded; 9 because of known or suspected psychiatric illness in a first or second degree relative, 4 because the NPC met one or more of the ARMS criteria, and 1 because of a combination of a history of depressive illness and drug abuse in the NPC.

7.2.2. Test battery Inclusion was followed by the assessment of a comprehensive test battery, which included the assessment of psychiatric, psychological, neurocognitive, neurophysiological and brain morphological variables. To monitor the development of psychotic symptoms and/or transition to psychosis, the SIPS and BSABS-P screening interviews were repeated after 9, 18 and 24 months. The 24-months assessment also included assessment of neurophysiological variables and structural MRI (see Table 6 and Appendix A). A large part of the T0 test battery which was used in the high-risk groups was also used in the NPC sample. After 24 months, the NPC participants were asked to participate in a follow-up assessment of symptomatology, neurophysiological and brain morphological variables.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 26

Mirjam Sprong | Adolescents at risk of psychosis

8. Outline of this dissertation The first step in comparing potential vulnerability markers for psychosis in two groups of high-risk adolescents with different pathways to psychosis was to compare high-risk symptoms and traits of ARMS adolescents and MCDD adolescents (Chapter 2). Because the ARMS group was defined by the presence of prodromal symptoms and the MCDD group was not, higher levels of these symptoms were expected in the first group than in the latter. Since schizotypal traits have been shown to reflect a biological-genetic vulnerability to schizophrenia or psychosis-proneness (Vollema et al. 2002), we expected that both high-risk groups would differ from NPCs regarding these traits. In addition to the data collected at the UMC site, data on 31 of the 12- to 18-year old ARMS adolescents of the AMC site were available for analysis. The second step was to compare the two high-risk groups on some of the more established neurocognitive and behavioral vulnerability markers for schizophrenia, i.e. impairments of verbal memory, psychomotor functioning, various subdomains of executive functioning and social functioning (Chapter 3). We expected that the two high-risk groups would show similar neurocognitive impairments compared to NPCs. However, since the MCDD group was defined by the presence of disturbed social

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 27

Mirjam Sprong | Adolescents at risk of psychosis behavior and social insensitivity, and the ARMS group was not, higher levels of social impairment were expected in the former than in the latter. We additionally explored the interrelationships of neurocognitive and social impairments in the high-risk adolescents. For this chapter, we were also able to supplement our data with data on some of the 12- to 18-year old ARMS adolescents of the AMC site. Unfortunately, due to differences in operationalization of the some of the dependent variables between sites, not all of the neurocognitive data on the AMC participants were useable. In Chapters 4 and 5 we turn our focus towards the second aim of this dissertation, i.e. the exploration of social cognitive impairments as potential vulnerability markers for psychosis. Social cognition is defined as “the mental operations underlying social interactions, which include processes involved in perceiving, interpreting, and generating responses to the intentions, dispositions, and behaviors of others” (Green et al. 2005). Examples of social cognitive skills are the ability to recognize other people’s emotions, and the ability to attribute mental states such as thoughts, beliefs and intentions to others, allowing an individual to explain, manipulate and predict their behavior. The latter is known as Theory of Mind (ToM) or mentalizing. Multiple reviews have shown that individuals with schizophrenia have difficulties in identifying and discriminating between other people’s emotions (Edwards et al. 2002; Mandal et al. 1998; Mueser et al. 1997; Phillips and David 1995). There is also some, though inconsistent, evidence that emotion-processing impairment is a potential vulnerability marker for psychosis, because it has been observed in individuals with a susceptibility to psychosis, i.e. siblings of schizophrenia patients (Kee et al. 2004), and individuals with schizotypal personality disorder or elevated levels of schizotypal traits (Combs et al. 2006; Combs and Penn 2004; Green et al. 2001 and 2003; Mikhailova et al. 1996; Poreh et al. 1994; Waldeck and Miller 2000). Also, associations between schizotypal traits and emotion processing performance have been described (Green and Williams 2000a and 2000b; Meyer and Shean 2006; Van 't Wout et al. 2004). In Chapter 4 the hypothesis that facial affect processing is impaired in adolescents at highrisk for psychosis is tested. The building-block view of social cognition states that adequate “lower-level”, i.e. nonsocial, neurocognitive skills such as attention/working memory, abstract visuospatial processing and face recognition represent a necessary - but not sufficient - condition for “higher-level”, social neurocognitive skills such as the recognition of facial emotions. In Chapter 4 we explore the evidence for this view. We expected that each of the lowerlevel neurocognitive skills would contribute additional variance to facial emotion processing performance. At the start of the project in 2002, there were many studies reporting on impairment of ToM in schizophrenia, but there was little evidence to suggest that it may also be a vulnerability marker for psychosis. We decided to start with a meta-analysis to analyze

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 28

Mirjam Sprong | Adolescents at risk of psychosis the magnitude of the impairment in schizophrenia, and to explore the effects of study characteristics on the findings. Meta-analyses have often been criticized for comparing apples and oranges, i.e. for summarizing and integrating findings from studies that do not really deal with the same constructs, or that have used different research designs. Another criticism is that study findings of different methodological qualities are combined, sometimes negatively referred to as the “garbage in, garbage out” problem. However, provided that they are carefully executed, meta-analyses also have considerable strengths. Firstly, a meta-analysis is an extremely structured and explicit type of review of study findings. Secondly, it produces effect size estimates with considerably more statistical power than the individual studies. Thirdly, it often allows for analyzing some of the effects of study characteristics on the observed effect sizes. In Chapter 5 the results of this meta-analysis are reported. We also collected data on ToM performance in our high-risk groups (Appendix A), but these data have not yet been analyzed. In Chapter 6, the presented findings will be evaluated and suggestions for future research will be discussed.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 29

Mirjam Sprong | Adolescents at risk of psychosis

References Ad-Dab'bagh,Y. and Greenfield,B., 2001. Multiple complex developmental disorder: the "multiple and complex" evolution of the "childhood borderline syndrome" construct. Journal of the American Academy of Child and Adolescent Psychiatry 40, 954-964. Addington,J., 2004. The diagnosis and assessment of individuals prodromal for schizophrenic psychosis. CNS Spectrums 9, 588-594. Aleman,A., Kahn,R.S., and Selten,J.P., 2003. Sex Differences in the Risk of Schizophrenia: Evidence from meta-analysis. Archives of General Psychiatry 60, 565-571. American Psychiatric Association, 1994. Diagnostic and statistical manual of mental disorders (4th edition). Washington DC: Author. Arinami,T., 2006. Analyses of the associations between the genes of 22q11 deletion syndrome and schizophrenia. Journal of Human Genetics 51, 1037-1045. Asarnow,J.R., 2005. Childhood-onset schizotypal disorder: a follow-up study and comparison with childhood-onset schizophrenia. Journal of Child and Adolescent Psychopharmacology 15, 395-402. Baker,K.D. and Skuse,D.H., 2005. Adolescents and young adults with 22q11 deletion syndrome: psychopathology in an at-risk group. The British Journal of Psychiatry 186, 115-120. Bechdolf,A., Phillips,L.J., Francey,S.M., Leicester,S., Morrison,A.P., Veith,V., Klosterkötter,J., and McGorry,P.D., 2006. Recent approaches to psychological interventions for people at risk of psychosis. European Archives of Psychiatry and Clinical Neuroscience 256, 159-173. Benvenuti,A., Rucci,P., Ravani,L., Gonnelli,C., Frank,E., Balestrieri,M., Sbrana,A., Dell'Osso,L., and Cassano,G.B., 2005. Psychotic features in borderline patients: is there a connection to mood dysregulation? Bipolar Disorders 7, 338-343. Bijl,R.V., De Graaf,R., Ravelli,A., Smit,F., and Vollebergh,W.A., 2002. Gender and age-specific first incidence of DSM-III-R psychiatric disorders in the general population. Results from the Netherlands Mental Health Survey and Incidence Study (NEMESIS). Social Psychiatry and Psychiatric Epidemiology 37, 372-379. Bleuler,E., 1911. Dementia praecox, or the group of schizophrenias, translated by J. Zinkin. New York: International Universities Press. Bleuler,M., 1978. The schizophrenic disorders: long-term patient and family studies. Translation of Die schizophrenen Geistesstörungen im Lichte langjähriger Kranken- und Familiengeschichten by Georg Thieme Verlag, Stuttgart, 1972, translated by S.M. Clemens. New Haven: Yale University Press.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 30

Mirjam Sprong | Adolescents at risk of psychosis Buitelaar,J.K. and Van der Gaag,R.J., 1998. Diagnostic rules for children with PDD-NOS and multiple complex developmental disorder. Journal of Child Psychology and Psychiatry, and Allied Disciplines 39, 911-919. Cannon,T.D., Cadenhead,K., Cornblatt,B., Woods,S.W., Addington,J., Walker,E., Seidman,L.J., Perkins,D., Tsuang,M., McGlashan,T., and Heinssen,R., 2008. Prediction of psychosis in youth at high clinical risk: a multisite longitudinal study in North America. Archives of General Psychiatry 65, 28-37. Clarke,D.J., Littlejohns,C.S., Corbett,J.A., and Joseph,S., 1989. Pervasive developmental disorders and psychoses in adult life. The British Journal of Psychiatry 155, 692-699. Cohen,D.J., Paul,R., and Volkmar,F.R., 1986. Issues in the classification of pervasive and other developmental disorders: toward DSM-IV. Journal of the American Academy of Child and Adolescent Psychiatry 25, 213-220. Cohen,D.J., Towbin,K.E., Mayes,L., and Volkmar,F., 1994. Developmental psychopathology of Multiplex Developmental Disorder. In: S.L. Friedman and H.C. Haywood (Series Ed.), Developmental follow-up: concepts, genres, domains, and methods. New York: Academic Press Inc., pp. 155-179. Combs,D.R., Michael,C.O., and Penn,D.L., 2006. Paranoia and emotion perception across the continuum. The British Journal of Clinical Psychology 45, 19-31. Combs,D.R. and Penn,D.L., 2004. The role of subclinical paranoia on social perception and behavior. Schizophrenia Research 69, 93-104. Cornblatt,B., Lencz,T., and Obuchowski,M., 2002. The schizophrenia prodrome: treatment and high-risk perspectives. Schizophrenia Research 54, 177-186. Cornblatt,B. and Obuchowski,M., 1997. Update of high-risk research: 1987-1997. International Review of Psychiatry 9, 437-447. Costello,C.G., 1992. Research on symptoms versus research on syndromes. Arguments in favour of allocating more research time to the study of symptoms. The British Journal of Psychiatry 160, 304-308. Davies,N., Russell,A., Jones,P., and Murray,R.M., 1998. Which characteristics of schizophrenia predate psychosis? Journal of Psychiatric Research 32, 121-131. De Bruin,E.I., De Nijs,P.F., Verheij,F., Hartman,C.A., and Ferdinand,R.F., 2007. Multiple Complex Developmental Disorder Delineated from PDD-NOS. Journal of Autism and Developmental Disorders 37, 1181-1191.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 31

Mirjam Sprong | Adolescents at risk of psychosis Debbane,M., Glaser,B., David,M.K., Feinstein,C., and Eliez,S., 2006. Psychotic symptoms in children and adolescents with 22q11.2 deletion syndrome: neuropsychological and behavioral implications. Schizophrenia Research 84, 187-193. DeLisi,L.E., Friedrich,U., Wahlstrom,J., Boccio-Smith,A., Forsman,A., Eklund,K., and Crow,T.J., 1994. Schizophrenia and sex chromosome anomalies. Schizophrenia Bulletin 20, 495-505. DeLisi,L.E., Maurizio,A.M., Svetina,C., Ardekani,B., Szulc,K., Nierenberg,J., Leonard,J., and Harvey,P.D., 2005. Klinefelter's syndrome (XXY) as a genetic model for psychotic disorders. American Journal of Medical Genetics. Part B: Neuropsychiatric Genetics 135, 15-23. Diwadkar,V.A., Prasad,K.M., and Keshavan,M.S., 2004. Approaches for adolescents with an affected family member with schizophrenia. Current Psychiatry Reports 6, 296-302. Dowson,J.H., Sussams,P., Grounds,A.T., and Taylor,J., 2002. Associations of self-reported past "psychotic" phenomena with features of personality disorders. Comprehensive Psychiatry 41, 42-48. Edwards,J., Jackson,H.J., and Pattison,P.E., 2002. Emotion recognition via facial expression and affective prosody in schizophrenia: a methodological review. Clinical Psychology Review 22, 789-832. Ellison,Z., van Os,J., and Murray,R., 1998. Special feature: childhood personality characteristics of schizophrenia: manifestations of, or risk factors for, the disorder? Journal of Personality Disorders 12, 247-261. Erlenmeyer-Kimling,L., 2000. Neurobehavioral deficits in offspring of schizophrenic parents: liability indicators and predictors of illness. American Journal of Medical Genetics 97, 65-71. Fuller Torrey,E., Bowler,A.E., Taylor,E.H., and Gottesman,I.I., 1994. Schizophrenia and manic-depressive disorder. The biological roots of mental illness as revealed by the landmark study of identical twins. New York: BasicBooks. Fusar-Poli,P., Perez,J., Broome,M., Borgwardt,S., Placentino,A., Caverzasi,E., Cortesi,M., Veggiotti,P., Politi,P., Barale,F., and McGuire,P., 2007. Neurofunctional correlates of vulnerability to psychosis: a systematic review and meta-analysis. Neuroscience and Biobehavioral Reviews 31, 465-484. Green,M.F., Olivier,B., Crawley,J.N., Penn,D.L., and Silverstein,S., 2005. Social cognition in schizophrenia: recommendations from the measurement and treatment research to improve cognition in schizophrenia new approaches conference. Schizophrenia Bulletin 31, 882-887. Green,M.J. and Williams,L.M., 2000a. Affect identification in schizotypy. Schizophrenia Research 41, 288-289.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 32

Mirjam Sprong | Adolescents at risk of psychosis Green,M.J. and Williams,L.M., 2000b. Processing of threat-related affect is delayed in delusion-prone individuals. Schizophrenia Research 41, 289. Green,M.J., Williams,L.M., and Davidson,D., 2003. Visual scanpaths and facial affect recognition in delusion-prone individuals: increased sensitivity to threat? Cognitive Neuropsychiatry. 8, 19-41. Green,M.J., Williams,L.M., and Davidson,D.J., 2001. Processing of threat-related affect is delayed in delusion-prone individuals. The British Journal of Clinical Psychology 40, 157-165. Gross,G., 1997. The onset of schizophrenia. Schizophrenia Research 28, 187-198. Häfner,H., Löffler,W., Maurer,K., Hambrecht,M., and an der Heiden,W., 1999. Depression, negative symptoms, social stagnation and social decline in the early course of schizophrenia. Acta Psychiatrica Scandinavica 100, 105-118. Häfner,H., Maurer,K., Löffler,W., van der Heiden,W., Munk-Jørgensen,P., Hambrecht,M., and RiecherRössler,A., 1998. The ABC Schizophrenia Study: a preliminary overview of the results. Social Psychiatry and Psychiatric Epidemiology 33, 380-386. Hambrecht,M., Lammertink,M., Klosterkötter,J., Matuschek,E., and Pukrop,R., 2002. Subjective and objective neuropsychological abnormalities in a psychosis prodrome clinic. The British Journal of Psychiatry 181, S30-S37. Hanssen,M.S., Bijl,R.V., Vollebergh,W., and van Os,J., 2003. Self-reported psychotic experiences in the general population: a valid screening tool for DSM-III-R psychotic disorders? Acta Psychiatrica Scandinavica 107, 369-377. Haroun,N., Dunn,L., Haroun,A., and Cadenhead,K.S., 2006. Risk and protection in prodromal schizophrenia: ethical implications for clinical practice and future research. Schizophrenia Bulletin 32, 166-178. Jablensky,A., 2005a. Boundaries of mental disorders. Current Opinion in Psychiatry 18, 653-658. Jablensky,A., 2005b. Categories, dimensions and prototypes: critical issues for psychiatric classification. Psychopathology 38, 201-205. Jackson,H.J., McGorry,P.D., and Dudgeon,P., 1995. Prodromal symptoms of schizophrenia in first-episode psychosis: prevalence and specificity. Comprehensive Psychiatry 36, 241-250. Jacobsen,L.K. and Rapoport,J.L., 1998. Research update: childhood-onset schizophrenia: implications of clinical and neurobiological research. Journal of Child Psychology and Psychiatry, and Allied Disciplines 39, 101-113.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 33

Mirjam Sprong | Adolescents at risk of psychosis Jansen,L.M., Gispen-de Wied,C.C., Gademan,P.J., De Jonge,R.C., Can der Linden,J.A., and Kahn,R.S., 1998. Blunted cortisol response to a psychosocial stressor in schizophrenia. Schizophrenia Research 33, 87-94. Jansen,L.M., Gispen-de Wied,C.C., Van der Gaag,R.J., Ten Hove,F., Willemsen-Swinkels,S.W., Harteveld,E., and Van Engeland,H., 2000. Unresponsiveness to psychosocial stress in a subgroup of autistic-like children, multiple complex developmental disorder. Psychoneuroendocrinology. 25, 753-764. Jansen,L.M., Gispen-de Wied,C.C., Van der Gaag,R.J., and Van Engeland,H., 2003. Differentiation between autism and multiple complex developmental disorder in response to psychosocial stress. Neuropsychopharmacology 28, 582-590. Jones,P.B. and Tarrant,C.J., 2000. Developmental precursors and biological markers for schizophrenia and affective disorders: specificity and public health implications. European Archives of Psychiatry and Clinical Neuroscience 250, 286-291. Kaplan,H.I., Sadock,B.J., and Grebb,J.A., 1994. Kaplan and Sadock's synopsis of psychiatry (7th edition). Baltimore: Williams and Wilkins. Kee,K.S., Horan,W.P., Mintz,J., and Green,M.F., 2004. Do the siblings of schizophrenia patients demonstrate affect perception deficits? Schizophrenia Research 67, 87-94. Keshavan,M.S., Diwadkar,V.A., Montrose,D.M., Rajarethinam,R., and Sweeney,J.A., 2005. Premorbid indicators and risk for schizophrenia: a selective review and update. Schizophrenia Research 79, 45-57. Kessler,R.C., Amminger,G.P., Aguilar-Gaxiola,S., Alonso,J., Lee,S., and Ustun,T.B., 2007. Age of onset of mental disorders: a review of recent literature. Current Opinion in Psychiatry 20, 359-364. Kirkbride,J.B., Fearon,P., Morgan,C., Dazzan,P., Morgan,K., Tarrant,J., Lloyd,T., Holloway,J., Hutchinson,G., Leff,J.P., Mallett,R.M., Harrison,G.L., Murray,R.M., and Jones,P.B., 2006. Heterogeneity in incidence rates of schizophrenia and other psychotic syndromes: findings from the 3-center ÆSOP study. Archives of General Psychiatry 63, 250-258. Klosterkötter,J., Hellmich,M., Steinmeyer,E.M., and Schultze-Lutter,F., 2001. Diagnosing schizophrenia in the initial prodromal phase. Archives of General Psychiatry 58, 158-164. Klosterkötter,J., Ruhrmann,S., Schultze-Lutter,F., Salokangas,R.K., Linszen,D., Birchwood,M., Juckel,G., Morrison,A., Vazquez-Barquero,J.L., Hambrecht,M., and Von Reventlow,H., 2005. The European Prediction of Psychosis Study (EPOS): integrating early recognition and intervention in Europe. World Psychiatry 4, 161-167.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 34

Mirjam Sprong | Adolescents at risk of psychosis Klosterkötter,J., Schultze-Lutter,F., Gross,G., Huber,G., and Steinmeyer,E.M., 1997. Early self-experienced neuropsychological deficits and subsequent schizophrenic diseases: an 8-year average follow-up prospective study. Acta Psychiatrica Scandinavica 95, 396-404. Konstantareas,M.M. and Hewitt,T., 2001. Autistic disorder and schizophrenia: diagnostic overlaps. Journal of Autism and Developmental Disorders 31, 19-28. Kremen,W.S., Seidman,L.J., Pepple,J.R., Lyons,M.J., Tsuang,M.T., and Faraone,S.V., 1994. Neuropsychological risk indicators for schizophrenia: a review of family studies. Schizophrenia Bulletin 20, 103-119. Kumra,S., Jacobson,L.K., Lenane M., Zahn,T.P., Wiggs,E., Alaghband-Rad,J., Castellanos,F.X., Frazier,J.A., McKenna K., Gordon,C.T., Smith,A., Hamburger,S., and Rapoport,J.L., 1998a. "Multidimensionally impaired disorder": is it a variant of very early-onset schizophrenia? Journal of the American Academy of Child and Adolescent Psychiatry 37, 91-99. Kumra,S., Wiggs,E., Krasnewich,D., Meck,J., Smith,A.C., Bedwell,J., Fernandez,T., Jacobsen,L.K., Lenane,M., and Rapoport,J.L., 1998b. Brief report: association of sex chromosome anomalies with childhood-onset psychotic disorders. Journal of the American Academy of Child and Adolescent Psychiatry 37, 292-296. Kunugi,H., Lee,K.B., and Nanko,S., 1999. Cytogenetic findings in 250 schizophrenics: evidence confirming an excess of the X chromosome aneuploidies and pericentric inversion of chromosome 9. Schizophrenia Research 40, 43-47. Lord,C., Rutter,M., and Le Couteur,A., 1994. Autism Diagnostic Interview-Revised (ADI-R): a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. Journal of Autism and Developmental Disorders 24, 659-685. Mäki,P., Veijola,J., Jones,P.B., Murray,G.K., Koponen,H., Tienari,P., Miettunen,J., Tanskanen,P., Wahlberg,K.E., Koskinen,J., Lauronen,E., and Isohanni,M., 2005. Predictors of schizophrenia: a review. British Medical Bulletin 73-74, 1-15. Mandal,M.K., Pandey,R., and Prasad,A.B., 1998. Facial expressions of emotions and schizophrenia: a review. Schizophrenia Bulletin 24, 399-412. Marshall,M., Lewis,S., Lockwood,A., Drake,R., Jones,P., and Croudace,T., 2005. Association between duration of untreated psychosis and outcome in cohorts of first-episode patients: a systematic review. Archives of General Psychiatry 62, 975-983. McGlashan, T. H., Miller, T. J, and Woods, S. W. Structured Interview for Prodromal Syndromes (SIPS) version 3.0, 2001. New Haven: PRIME Research Clinic, Yale School of Medicine.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 35

Mirjam Sprong | Adolescents at risk of psychosis McGorry,P.D., McKenzie,D., Jackson,H.J., Waddell,F., and Curry,C., 2000. Can we improve the diagnostic efficiency and predictive power of prodromal symptoms for schizophrenia? Schizophrenia Research 42, 91-100. Meyer,J. and Shean,G., 2006. Social-cognitive functioning and schizotypal characteristics. The Journal of Psychology 140, 199-207. Mikhailova,E.S., Vladimirova,T.V., Iznak,A.F., Tsusulkovskaya,E.J., and Sushko,N.V., 1996. Abnormal recognition of facial expression of emotions in depressed patients with major depression disorder and schizotypal personality disorder. Biological Psychiatry 40, 697-705. Miller,T.J., McGlashan,T.H., Rosen,J.L., Cadenhead,K., Cannon,T., Ventura,J., McFarlane,W., Perkins,D.O., Pearlson,G.D., and Woods,S.W., 2003. Prodromal assessment with the structured interview for prodromal syndromes and the scale of prodromal symptoms: predictive validity, interrater reliability, and training to reliability. Schizophrenia Bulletin 29, 703-715. Miller,T.J., McGlashan,T.H., Rosen,J.L., Somjee,L., Markovich,P.J., Stein,K., and Woods,S.W., 2002. Prospective diagnosis of the initial prodrome for schizophrenia based on the Structured Interview for Prodromal Syndromes: preliminary evidence of interrater reliability and predictive validity. The American Journal of Psychiatry 159, 863-865. Miller,T.J., McGlashan,T.H., Woods,S.W., Stein,K., Driesen,N., Corcoran,C.M., Hoffman,R., and Davidson,L., 1999. Symptom assessment in schizophrenic prodromal states. The Psychiatric Quarterly 70, 273-287. Mojtabai,R. and Rieder,R.O., 1998. Limitations of the symptom-oriented approach to psychiatric research. The British Journal of Psychiatry 173, 198-202. Moller,P. and Husby,R., 2000. The initial prodrome in schizophrenia: searching for naturalistic core dimensions of experience and behavior. Schizophrenia Bulletin 26, 217-232. Mouridsen,S.E., Rich,B., and Isager,T., 2008. Psychiatric disorders in adults diagnosed as children with atypical autism. A case control study. Journal of Neural Transmission 115, 135-138.

Mueser,K.T., Penn,D.L., Blanchard,J.J., and Bellack,A.S., 1997. Affect recognition in schizophrenia: a synthesis of findings across three studies. Psychiatry 60, 301-308. Mullen,R., 2003. Delusions: the continuum versus category debate. The Australian and New Zealand Journal of Psychiatry 37, 505-511. Murphy,K.C., Jones,L.A., and Owen,M.J., 1999. High rates of schizophrenia in adults with velo-cardiofacial syndrome. Archives of General Psychiatry 56, 940-945.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 36

Mirjam Sprong | Adolescents at risk of psychosis Murphy,K.C. and Owen,M.J., 2001. Velo-cardio-facial syndrome: a model for understanding the genetics and pathogenesis of schizophrenia. The British Journal of Psychiatry 179, 397-402. Murray,R.M., O'Callaghan,E., Castle,D.J., and Lewis,S.W., 1992. A neurodevelopmental approach to the classification of schizophrenia. Schizophrenia Bulletin 18, 319-332. Neumann,C.S., Grimes,K., Walker,E.F., and Baum,K., 1995. Developmental pathways to schizophrenia: behavioral subtypes. Journal of Abnormal Psychology 104, 558-566. Nieman,D., Becker,H., Van de Fliert,R., Plat,N., Bour,L., Koelman,H., Klaassen,M., Dingemans,P., Niessen,M., and Linszen,D., 2007. Antisaccade task performance in patients at ultra high risk for developing psychosis. Schizophrenia Research 95, 54-60. Niemi,L.T., Suvisaari,J.M., Tuulio-Henriksson,A., and Lonnqvist,J.K., 2003. Childhood developmental abnormalities in schizophrenia: evidence from high-risk studies. Schizophrenia Research 60, 239-258. Norman,R.M., Lewis,S.W., and Marshall,M., 2005. Duration of untreated psychosis and its relationship to clinical outcome. The British Journal of Psychiatry Supplement 48, s19-s23. Norman,R.M. and Malla,A.K., 2001. Duration of untreated psychosis: a critical examination of the concept and its importance. Psychological Medicine 31, 381-400. Offord,D.R. and Cross,L.A., 1969. Behavioral antecedents of adult schizophrenia: a review. Archives of General Psychiatry 21, 267-283. Olin,S.C. and Mednick,S.A., 1996. Risk factors of psychosis: identifying vulnerable populations premorbidly. Schizophrenia Bulletin 22, 223-240. Olsen,K.A. and Rosenbaum,B., 2006a. Prospective investigations of the prodromal state of schizophrenia: assessment instruments. Acta Psychiatrica Scandinavica 113, 273-282. Olsen,K.A. and Rosenbaum,B., 2006b. Prospective investigations of the prodromal state of schizophrenia: review of studies. Acta Psychiatrica Scandinavica 113, 247-272. Phillips,L.J., McGorry,P.D., Yung,A.R., McGlashan,T.H., Cornblatt,B., and Klosterkötter,J., 2005. Prepsychotic phase of schizophrenia and related disorders: recent progress and future opportunities. The British Journal of Psychiatry Supplement 48, s33-s44. Phillips,L.J., Yung,A.R., Yuen,H.P., Pantelis,C., and McGorry,P.D., 2002. Prediction and prevention of transition to psychosis in young people at incipient risk for schizophrenia. American Journal of Medical Genetics 114, 929-937.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 37

Mirjam Sprong | Adolescents at risk of psychosis Phillips,M.L. and David,A.S., 1995. Facial processing in schizophrenia and delusional misidentification: cognitive neuropsychiatric approaches. Schizophrenia Research 17, 109-114. Poreh,A.M., Whitman,R.D., Weber,M., and Ross,T., 1994. Facial recognition in hypothetically schizotypic college students. The role of generalized poor performance. The Journal of Nervous and Mental Disease 182, 503-507. Pukrop,R., Ruhrmann,S., Schultze-Lutter,F., Bechdolf,A., Brockhaus-Dumke,A., and Klosterkötter,J., 2007. Neurocognitive indicators for a conversion to psychosis: comparison of patients in a potentially initial prodromal state who did or did not convert to a psychosis. Schizophrenia Research 92, 116-125. Pukrop,R.,

Schultze-Lutter,F.,

Ruhrmann,S.,

Brockhaus-Dumke,A.,

Tendolkar,I.,

Bechdolf,A.,

Matuschek,E., and Klosterkötter,J., 2006. Neurocognitive functioning in subjects at risk for a first episode of psychosis compared with first- and multiple-episode schizophrenia. Journal of Clinical and Experimental Neuropsychology 28, 1388-1407. Rodriguez Solano,J.J. and Gonzalez,D.C., 2000. Premorbid personality disorders in schizophrenia. Schizophrenia Research 44, 137-144. Rossi,A., Pollice,R., Daneluzzo,E., Marinangeli,M.G., and Stratta,P., 2000. Behavioral neurodevelopment abnormalities and schizophrenic disorder: a retrospective evaluation with the Childhood Behavior Checklist (CBCL). Schizophrenia Research 44, 121-128. Rössler,W., Salize,H.J., Van Os,J., and Riecher-Rössler,A., 2005. Size of burden of schizophrenia and psychotic disorders. European Neuropsychopharmacology 15, 399-409. Schothorst,P.F., Emck,C., and Van Engeland,H., 2006. Characteristics of early psychosis. Comprehensive Psychiatry 47, 438-442. Schultze-Lutter,F. and Klosterkötter,J., 2002. Bonn Scale for the Assessment of Basic Symptoms Prediction list (BSABS-P). Cologne: University of Cologne. Simon,A.E., Cattapan-Ludewig,K., Zmilacher,S., Arbach,D., Gruber,K., Dvorsky,D.N., Roth,B., Isler,E., Zimmer,A., and Umbricht,D., 2007. Cognitive functioning in the schizophrenia prodrome. Schizophrenia Bulletin 33, 761-771. Simon,A.E., Dvorsky,D.N., Boesch,J., Roth,B., Isler,E., Schueler,P., Petralli,C., and Umbricht,D., 2006. Defining subjects at risk for psychosis: a comparison of two approaches. Schizophrenia Research 81, 83-90. Sitskoorn,M.M., Aleman,A., Ebisch,S.J., Appels,M.C., and Kahn,R.S., 2004. Cognitive deficits in relatives of patients with schizophrenia: a meta-analysis. Schizophrenia Research 71, 285-295. Snitz,B.E., Macdonald,A.W., III, and Carter,C.S., 2006. Cognitive deficits in unaffected first-degree relatives of schizophrenia patients: a meta-analytic review of putative endophenotypes. Schizophrenia Bulletin 32, 179-194.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 38

Mirjam Sprong | Adolescents at risk of psychosis Sporn,A.L., Addington,A.M., Gogtay,N., Ordonez,A.E., Gornick,M., Clasen,L., Greenstein,D., Tossell,J.W., Gochman,P., Lenane,M., Sharp,W.S., Straub,R.E., and Rapoport,J.L., 2004. Pervasive developmental disorder and childhood-onset schizophrenia: comorbid disorder or a phenotypic variant of a very early onset illness? Biological Psychiatry 55, 989-994. Stahlberg,O., Soderstrom,H., Rastam,M., and Gillberg,C., 2004. Bipolar disorder, schizophrenia, and other psychotic disorders in adults with childhood onset AD/HD and/or autism spectrum disorders. Journal of Neural Transmission 111, 891-902. Szoke,A., Schurhoff,F., Mathieu,F., Meary,A., Ionescu,S., and Leboyer,M., 2005. Tests of executive functions in first-degree relatives of schizophrenic patients: a meta-analysis. Psychological Medicine 35, 771-782. Tantam,D., 1988. Lifelong eccentricity and social isolation I: psychiatric, social, and forensic aspects. The British Journal of Psychiatry 153, 777-782. Towbin,K.E., Dykens,E.M., Pearson,G.S., and Cohen,D.J., 1993. Conceptualizing "borderline syndrome of childhood" and "childhood schizophrenia" as a developmental disorder. Journal of the American Academy of Child and Adolescent Psychiatry 32, 775-782. Trandafir,A., Meary,A., Schurhoff,F., Leboyer,M., and Szoke,A., 2006. Memory tests in first-degree adult relatives of schizophrenic patients: a meta-analysis. Schizophrenia Research 81, 217-226. Van 't Wout,M., Aleman,A., Kessels,R.P.C., Laroi,F., and Kahn,R.S., 2004. Emotional processing in a nonclinical psychosis-prone sample. Schizophrenia Research 68, 271-281. Van der Gaag,R.J., Buitelaar,J., Van den Ban,E., Bezemer,M., Njio,L., and Van Engeland,H., 1995. A controlled multivariate chart review of multiple complex developmental disorder. Journal of the American Academy of Child and Adolescent Psychiatry 34, 1096-1106. Van Engeland,H. and Van der Gaag,R.J., 1994. MCDD in childhood: a precursor of schizophrenic spectrum disorders. Schizophrenia Research 11, 197. Van Rijn,S., Aleman,A., Swaab,H., and Kahn,R., 2006. Klinefelter's syndrome (karyotype 47,XXY) and schizophrenia-spectrum pathology. The British Journal of Psychiatry 189, 459-460. Vollema,M.G., Sitskoorn,M.M., Appels,M.C., and Kahn,R.S., 2002. Does the Schizotypal Personality Questionnaire reflect the biological-genetic vulnerability to schizophrenia? Schizophrenia Research 54, 39-45. Vollmer-Larsen,A., Handest,P., and Parnas,J., 2007. Reliability of measuring anomalous experience: the Bonn Scale for the Assessment of Basic Symptoms. Psychopathology 40, 345-348.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 39

Mirjam Sprong | Adolescents at risk of psychosis Vorstman,J.A., Morcus,M.E., Duijff,S.N., Klaassen,P.W., Heineman-de Boer,J.A., Beemer,F.A., Swaab,H., Kahn,R.S., and Van Engeland,H., 2006. The 22q11.2 deletion in children: high rate of autistic disorders and early onset of psychotic symptoms. Journal of the American Academy of Child and Adolescent Psychiatry 45, 1104-1113. Waldeck,T.L. and Miller,L.S., 2000. Social skills deficits in schizotypal personality disorder. Psychiatry Research 93, 237-246. Whalley,H.C., Whyte,M.C., Johnstone,E.C., and Lawrie,S.M., 2005. Neural correlates of enhanced genetic risk for schizophrenia. The Neuroscientist 11, 238-249. Widiger,T.A., 2005. A dimensional model of psychopathology. Psychopathology 38, 211-214. Wolff,S., 1995. Loners: the life path of unusual children. London: Routledge. Yung,A.R., 2007. Identification and treatment of the prodromal phase of psychotic disorders: perspectives from the PACE Clinic. Early Intervention in Psychiatry 1, 224-235. Yung,A.R. and McGorry,P.D., 1996. The prodromal phase of first-episode psychosis: past and current conceptualizations. Schizophrenia Bulletin 22, 353-370. Yung,A.R., Phillips,L.J., Yuen,H.P., Francey,S.M., McFarlane,C.A., Hallgren,M., and McGorry,P.D., 2003. Psychosis prediction: 12-month follow up of a high-risk ("prodromal") group. Schizophrenia Research 60, 21-32. Yung,A.R., Phillips,L.J., Yuen,H.P., and McGorry,P.D., 2004. Risk factors for psychosis in an ultra high-risk group: psychopathology and clinical features. Schizophrenia Research 67, 131-142. Yung,A.R., Stanford,C., Cosgrave,E., Killackey,E., Phillips,L., Nelson,B., and McGorry,P.D., 2006. Testing the Ultra High Risk (prodromal) criteria for the prediction of psychosis in a clinical sample of young people. Schizophrenia Research 84, 57-66. Yung,A.R., Yuen,H.P., Berger,G., Francey,S., Hung,T.C., Nelson,B., Phillips,L., and McGorry,P., 2007. Declining transition rate in ultra high risk (prodromal) services: dilution or reduction of risk? Schizophrenia Bulletin 33, 673-681.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 40

Mirjam Sprong | Adolescents at risk of psychosis

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 41

Mirjam Sprong | Adolescents at risk of psychosis

Chapter 2

Pathways to psychosis: a comparison of the Pervasive Developmental Disorder subtype Multiple Complex Developmental Disorder and the “At Risk Mental State“

Mirjam Sprong a, Hiske Becker b, Patricia Schothorst a, Hanna Swaab c, Tim Ziermans a, Peter Dingemans b, Don Linszen b, Herman van Engeland a Schizophrenia Research (2008), 99: 38-47

a

Rudolf Magnus Institute of Neuroscience/Department of Child and Adolescent Psychiatry, University Medical Center Utrecht, the Netherlands b Department of Psychiatry, Academic Medical Center De Meren, Amsterdam, the Netherlands c Department of Clinical Child and Adolescent Studies, University of Leiden, the Netherlands

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 42

Mirjam Sprong | Adolescents at risk of psychosis

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 43

Mirjam Sprong | Adolescents at risk of psychosis

Abstract Background: The comparison of high-risk populations with different developmental pathways to psychosis may lend more insight into the heterogeneity of the manifestation of the psychotic syndrome, and possible differing etiological pathways. Aim: To compare high-risk traits and symptoms in two populations at risk for psychosis, i.e. (1) help-seeking adolescents presenting with prodromal symptoms meeting the criteria for At Risk Mental State (ARMS), and (2) adolescents with Multiple Complex Developmental Disorder (MCDD), a PDD-NOS subtype characterized by severe, early childhood-onset deficits in affect regulation, anxieties, disturbed social relationships, and thought disorder. Method: 80 ARMS and 32 MCDD adolescents (12-18 yrs) were compared on prodromal symptoms (Structured Interview of Prodromal Symptoms, and Bonn Scale for the Assessment of Basic Symptoms-Prediction list), and autism traits (Social Communication Questionnaire). In addition, both high-risk groups were compared with 82 nonpsychiatric controls on schizotypal traits (Schizotypal Personality QuestionnaireRevised). Results: Although the high-risk groups clearly differed in early developmental and treatment histories as well as autism traits, they did not differ with regard to schizotypal traits and basic symptoms, as well as disorganized and general prodromal symptoms. There were, however, group differences in positive and negative prodromal symptoms. Interestingly, 78% of the adolescents with MCDD met the research criteria for ARMS. Conclusion: These findings suggest that children diagnosed with MCDD are at high risk for developing psychosis later in life, and support the notion that there are different developmental pathways to psychosis. Follow-up research is needed to compare the rates of transition to psychosis in both high-risk groups.

1. Introduction Psychotic symptoms are not only part of the syndromes of schizophrenia and other psychotic disorders, but may also arise in other psychiatric disorders, in particular the affective disorders (American Psychiatric Association 1994). In addition, certain personality disorders (Benvenuti et al. 2005; Dowson et al. 2002; Rodriguez Solano and Gonzalez 2000), and genetic syndromes such as Klinefelter (DeLisi et al. 1994; Kunugi et al. 1999; Van Rijn et al. 2006) and 22q11-deletion syndrome (Baker and Skuse 2005; Debbane et al. 2006; Murphy et al. 1999; Vorstman et al. 2006) have been associated with elevated risks of psychotic symptoms and schizophrenia spectrum disorders. Retrospective studies have shown that the onset of overt psychosis is often preceded by prodromal signs and symptoms, including functional decline, subtle deviations in

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 44

Mirjam Sprong | Adolescents at risk of psychosis thought, emotion and perception, and subthreshold psychotic symptoms (e.g. Häfner et al. 1999; Schothorst et al. 2006). Over the past decade, the focus of attention in schizophrenia research has been widened to also include the prodromal phase. Projects are being set up all over the world to identify and offer treatment to prodromal individuals in the hope of preventing or delaying psychotic outbreak (e.g. Addington 2004; Bechdolf et al. 2006; Chong et al. 2004; Klosterkötter et al. 2005; McGlashan et al. 2003; McGorry et al. 2002; Ruhrmann et al. 2005). However, because the term “prodrome” can only be used in retrospect, the terms “ultra high-risk” or “clinical highrisk” or “At Risk Mental State” (ARMS) are used. The first results of these projects have indicated that ARMS individuals are indeed at imminent risk of psychosis, with transition rates ranging from 15% to 54% after 6 months to 1 year (e.g. Haroun et al. 2006; Miller et al. 2002). Another population at risk for psychosis consists of subjects with Multiple Complex Developmental Disorder (MCDD), a subtype of Pervasive Developmental Disorder - Not Otherwise Specified (PDD-NOS) which is characterized by early childhood-onset affect dysregulation, high levels of anxiety, social impairment, and thought disorder. This combination of symptoms has received various labels in the past, including borderline syndrome of childhood, multiplex developmental disorder, schizoid disorder, and schizotypal disorder (Ad-Dab'bagh and Greenfield 2001). Cohen et al. (1986, 1994) proposed a set of diagnostic criteria for MCDD (Table 1), which have later been refined by Towbin et al. (1993), and Buitelaar and Van der Gaag (1998). Follow-up of 55 children with MCDD revealed a considerably elevated risk of psychosis; 22% that had been followed until adolescence, and 64% that had been followed until young adulthood had developed schizophrenia-spectrum disorders (Van Engeland and Van der Gaag 1994).

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 45

Mirjam Sprong | Adolescents at risk of psychosis

The notion that some psychotic patients show premorbid behavioral abnormalities dates back to Bleuler (1911), and since then it has often been confirmed (e.g. Isohanni et al. 2000; Niemi et al. 2003). Furthermore, the fact that subjects with MCDD have severe impairments from early childhood, whereas the ARMS symptoms are identified in adolescents and young-adults who in most cases have been relatively inconspicuous as a child, suggests that there are different developmental pathways to psychosis. This is supported by a retrospective study in schizophrenia patients by Rossi et al. (2000) who identified two subgroups. The first displayed only minor behavioral abnormalities during

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 46

Mirjam Sprong | Adolescents at risk of psychosis childhood, which increased progressively over the years. The other already displayed severe behavioral abnormalities during childhood, which remained relatively stable over time. Corcoran et al. (2003), who retrospectively studied the evolution of symptoms in ARMS adolescents, also identified two subgroups. The largest subgroup had had an essentially normal development throughout childhood but displayed behavioral and personality changes in adolescence. The smaller subgroup was described as “never normal”. Research into precursors of psychosis leads to a better understanding of the pathogenesis, and a more accurate identification of those at high-risk. The comparison of these precursors in populations with different pathways to psychosis is of particular interest, because it may additionally lend more insight into the heterogeneity of the manifestation of the psychotic syndrome (Schmael et al. 2007). The aim of the present study is to explore whether ARMS adolescents and adolescents with prepubertal diagnoses of MCDD can be differentiated based on prodromal symptoms, and autism and schizotypal traits. First, because the ARMS group is defined by the presence of prodromal symptoms and the MCDD group is not, higher levels of these symptoms are expected in the first group than in the latter. Second, because MCDD is considered a subtype of PDD-NOS, more autism traits are expected in MCDD adolescents than in ARMS adolescents. Third, since schizotypal traits have been shown to reflect a biological-genetic vulnerability to schizophrenia or psychosis-proneness (Vollema et al. 2002), it is hypothesized that both high-risk groups differ from nonpsychiatric controls regarding these traits.

2. Method This study is part of the Dutch Prediction of Psychosis Study, a longitudinal research project that has been approved by the Dutch Central Committee on Research Involving Human Subjects. It is a cooperation between the Child and Adolescent Psychiatry Department of the University Medical Center (UMC), and the Psychiatry Department of the Academic Medical Center (AMC). The latter is part of the European Prediction of Psychosis Study (EPOS; Klosterkötter et al. 2005).

2.1 Subjects The ARMS group consisted of help-seeking adolescents who met one or more of the four EPOS inclusion criteria (Klosterkötter et al. 2005): (1) attenuated positive symptoms, (2) brief, limited, or intermittent psychotic symptoms, (3) a 30% reduction in overall level of social, occupational/school, and psychological functioning in the past year, combined with a genetic risk of psychosis, and (4) two or more of a selection of nine basic symptoms, i.e. subjective deficits in cognitive, perceptual, and motor functioning. The

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 47

Mirjam Sprong | Adolescents at risk of psychosis first three inclusion criteria were assessed with the Structured Interview for Prodromal Syndromes (SIPS; McGlashan et al. 2001). The fourth inclusion criterion was assessed with the Bonn Scale for the Assessment of Basic Symptoms-Prediction List (BSABS-P; Schultze-Lutter and Klosterkötter 2002). The MCDD group consisted of adolescents with prepubertal DSM-IV diagnoses of PDDNOS (American Psychiatric Association 1994), with the additional qualification of “meeting the criteria for MCDD”, implying early childhood-onset impairments in affect regulation, social behavior/sensitivity, and cognition (Cohen et al. 1994). Diagnoses were confirmed by expert clinical opinion (HvE, PS) after psychiatric examination including the Autism Diagnostic Interview-Revised (Lord et al. 1994), as well as a parent interview based on the diagnostic criteria for MCDD (Table 1), which was developed for internal use at the UMC. Consecutively, the MCDD criteria were rated using the information present in the medical records of the patients (PS, MS). The mean number of criteria met was 8.46 (SD = 2.60). Nonpsychiatric controls (NPCs) were recruited from secondary schools in the region of Utrecht. They were excluded if they had MCDD, met one of the ARMS criteria, or if they had a history of any psychiatric illness themselves, or in a first-degree relative, or a second-degree relative with a psychotic disorder. All participants were aged between 12 and 18 years. They all signed an informed consent, and for those younger than 16, parents co-signed. None of them had ever experienced a psychotic episode lasting more than one week, defined as the presence of positive symptoms that are seriously disorganizing, i.e. a score of 6 on any of the items of the SIPS Positive Symptoms subscale, or on the SIPS item “Odd behavior or appearance”. All had a level of verbal intellectual functioning (VIQ) ≥ 75. At the UMC, VIQ was assessed with the Wechsler Intelligence Scales (1997 and 2002). At the AMC, VIQ was estimated using the Dutch adaptation of the National Adult Reading Test (Nelson, 1982; Schmand et al. 1992). Since there was no relationship between site and VIQ (F(1,70) = 0.001; p = .972), the VIQ-data of the two sites were combined.

2.2 Prodromal symptoms The semi-structured SIPS interview was designed to assess a broad spectrum of prodromal signs and symptoms. It has 4 subscales: Positive (5 items), Negative (6 items), Disorganization (4 items), and General symptoms (4 items), and also includes a Global Assessment of Functioning (GAF-) scale with well-defined anchor points (McGlashan et al. 2001). Symptoms are scored on a 7-point scale from 0 (absent) through 6 (extreme/psychotic intensity). The distinction between a score of 5 (severe) and a score of 6 (psychotic) for the positive symptoms is mainly determined by “the lack of conviction regarding the externally generated, “real” nature of the symptom as well as the maintenance of insight regarding the sense that the experience is, in fact, a

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 48

Mirjam Sprong | Adolescents at risk of psychosis symptom” (Miller et al. 2003). The semi-structured BSABS-P interview was used to rate subjective disturbances, that have been found to be predictive for psychosis (Schultze-Lutter and Klosterkötter 2002). The 33 items are summarized in three subscales, i.e. Cognitive (11 items), Perceptual (19 items), and Motor disturbances (3 items). In line with the SIPS, a 7-point scoring scale has been developed to rate the presence and severity of the symptoms, from 0 (absent) through 6 (frequent/extreme).

2.3 Schizotypal traits The revised self-report Schizotypal Personality Questionnaire (SPQ-R) was used to assess schizotypal personality traits (Raine 1991; Vollema and Hoijtink 2000). Factor analyses have shown that the 74 items can be reduced to three latent variables corresponding with the positive, negative and disorganization dimensions of schizotypy (Raine et al. 1994; Vollema and Hoijtink 2000). At the UMC, the SPQ-R was slightly modified to better accommodate a young population (e.g. items referring to work were changed into school).

2.4 Autism traits At the UMC, the parent-completed Social Communication Questionnaire-lifetime version, formerly known as the Autism Screening Questionnaire, was used to assess the presence of autism traits in both high-risk groups (SCQ; Rutter et al. 2003; Warreyn and Roeyers 2001). It is a 40-item screening questionnaire for autism spectrum disorders, with a possible total score of 0-39 for verbal children. The items refer to core autistic behaviors, covering the areas of communication, reciprocal social interaction, and restricted and repetitive behaviors, with many of the items specifically referencing to behaviors between the fourth and fifth birthdays. Berument et al. (1999) showed that a cut-off of 15 discriminates PDD and non-PDD diagnoses well. Questionnaires with more than 4 omitted items were excluded from the analyses.

2.5 Data analysis Data distributions were checked for normality using the Kolmogorov-Smirnov test, and homogeneity of the variances using the Levene’s test, supplemented by visual inspections of the data distributions and residual plots. Hypotheses were tested using χ2 -tests and nonparametric tests. Possible confounding of age and gender was explored by nonparametric bivariate correlations. All analyses were two-tailed, and to reduce the risk of making Type I errors due to multiple testing, α was set at .01, and a Bonferroni-correction was applied to all post hoc comparisons. Effect sizes r were calculated (Field 2005) and rated following the widely used convention for appraising effect sizes in behavioral research; effect sizes of .10 were considered small, of .30 medium, and above .50 large (Cohen 1988).

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 49

Mirjam Sprong | Adolescents at risk of psychosis

3. Results 3.1. Baseline characteristics During the two-year recruitment phase, 327 adolescents between 12 and 18 years were referred to the two research sites. After consultation with the referring persons, 53 were considered ineligible for screening: 19 did not have “prodromal” signs or MCDD, 19 were outside the age range, 9 had already experienced a psychotic episode lasting more than one week, 4 had a VIQ < 75, 1 only had symptoms after the use of drugs, and 1 lived in a youth penitentiary facility. Of the remaining 274 referred adolescents, 132 were interviewed, of whom 80 met ARMS criteria and 32 had a diagnosis of MCDD. The other 142 were not interviewed: 88 refused to participate, in 29 cases the case manager requested not to approach his patient because of clinical considerations, and in 26 cases there were other reasons (e.g. change of case manager, not able to contact patient). Statistical comparisons revealed group differences regarding age, gender and VIQ (Table 2). The two high-risk groups had similar GAF-scores. As expected, the MCDD group had more early-onset behavioral problems than the ARMS group, exemplified by a larger proportion of subjects with a first mental health contact before age 6, which was broadly defined and included contacts with social workers, psychologists, and psychiatrists. Also, a large proportion of MCDD subjects had received special primary education, whereas the percentage of ARMS subjects receiving special primary education compared well with the general population. About 3% of all school-going children in the Netherlands received special education in 2005/2006 according to the Centre for Policy Related Statistics (2007).

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 50

Mirjam Sprong | Adolescents at risk of psychosis

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 51

Mirjam Sprong | Adolescents at risk of psychosis

3.2. At Risk Mental State criteria The rates of high-risk adolescents meeting each of the four subsets of ARMS criteria are reported in Table 3. Of the ARMS group, 43.8% met one, 45.0% met two, and 11.3% met three criteria. Although different inclusion criteria were used, i.e. having a childhood MCDD diagnosis, now in their adolescence 78.1% of the MCDD group also met at least one of the ARMS criteria; 50.0% met one, 25.0% met two, and 3.1% met three. The rate of first- or second-degree relatives with a psychotic disorder in the MCDD group was comparable to that in the ARMS group (12.9% and 13.0% respectively), but the genetic risk and drop in GAF-score criterion was met in none of the MCDD adolescents.

3.3. Prodromal symptoms The ARMS group reported higher levels of SIPS Positive and Negative symptoms than the MCDD group (Table 4), representing medium effect sizes. Further analyses revealed that relatively more ARMS adolescents than MCDD adolescents reported at least one elevated score (i.e. ≥ 3) on any of the items of the SIPS Positive symptoms scale (93.8% and 65.6% respectively, χ2 (1) = 14.77, p < .001). There were no differences between the two high-risk groups regarding the SIPS Disorganization and General symptoms scales, the BSABS-P summary scales, nor the percentages of subjects with elevated (i.e. ≥ 3) scores on any of the items of the BSABS-P scales.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 52

Mirjam Sprong | Adolescents at risk of psychosis

3.4. Schizotypal traits Group differences were observed for all three schizotypal factors (Table 5). Post hoc comparisons showed that there were no differences between the two high-risk groups. Both the ARMS and the MCDD group scored higher than the NPCs on all three factors, representing medium to large effect sizes.

3.5. Autism traits More autism traits were reported in the MCDD than in the ARMS group (Mdns 18 and 6 respectively, U = 112.0, p < .001). Using the experimental cut-off of 15 (Berument et al. 1999), 4.7% (n = 2) of the ARMS subjects and 71.4% (n = 20) of the MCDD subjects scored in the PDD-range.

3.6. Possible confounding of age and gender on symptomatology and traits No significant correlations between age and gender were observed when the two highrisk groups were combined (r = .076, p = .427), nor when the two high-risk groups were analyzed separately (ARMS: r = .038, p = .739; MCDD: r = .048, p = .796). In the combined high-risk sample, age was positively related to SIPS Positive symptoms (τ = .234, p < .001), but not to the other SIPS scales, the BSABS-P scales, nor the

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 53

Mirjam Sprong | Adolescents at risk of psychosis

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 54

Mirjam Sprong | Adolescents at risk of psychosis schizotypy scales. When the two high-risk samples were analyzed separately, the correlations between age and SIPS Positive symptoms no longer reached statistical significance (ARMS: τ = .164, p < .040; MCDD: τ = .069, p < .590), although the results suggest an increase with age in the ARMS group. In the combined high-risk sample, significant correlations were observed between gender and SIPS Positive symptoms (τ = .291, p < .001), SIPS General symptoms (τ = .269, p = .001), BSABS-P Perceptual disturbances (τ = .232; p = .005), and SPQ-R Positive schizotypy (τ = .287, p = .001). For all of these scales, higher levels were reported by girls than by boys (SIPS Positive symptoms: U = 874.5, p < .001; SIPS General symptoms: U = 931.0, p = .001; BSASB-P Perceptual disturbances: U = 892.5, p = .003; SPQ-R Positive scale: U = 657.0, p < .001). When the two high-risk groups were analyzed separately, none of these correlations reached statistical significance. Age was negatively related to autism traits (τ = -.288, p = .001) in the two high-risk groups combined. However, when the two high-risk groups were analyzed separately, the correlations did not reach statistical significance (ARMS: τ = .087, p = .423, MCDD: τ = .133, p = .331). Although the effects of gender on traits and symptoms appeared to be small, to exclude the possibility that the (lack of) group differences might be explained by gender differences, the analyses of sections 3.3. and 3.4. were repeated for only the male subjects. Because there were only 8 girls in the MCDD group, girls were not analyzed separately. The results are completely in line with the results when the girls were included. The difference between ARMS boys and MCDD boys was significant only for the SIPS Positive and Negative symptoms (Positive: U = 253.5, p = .001; Negative: U = 304.5, p = .008), but not for the other SIPS nor BSABS-P scales: SIPS Disorganized symptoms (U = 370.0, p = .092), SIPS General symptoms (U = 399.5, p = .166), BSABS-P Cognitive symptoms (U = 374.0, p = .173), BSABS-P Perceptual disturbances (U = 340.5, p = .087), BSABS-P Motor disturbances (U = 437.0, p = .472). There were group differences for all three SPQ-R scales (all p’s < .001). Two-by-two comparisons showed that boys of the two high-risk groups differed significantly from NPC boys on all three scales (all p’s < .001), and that ARMS and MCDD boys did not differ on any of the scales (Cognitiveperceptual: U = 360.5, p = .857; Interpersonal: U = 412.0; p = 1.000; Disorganized: U = 308.5; p = .179).

4. Discussion Contrary to the first hypothesis, ARMS and MCDD adolescents did not differ regarding subjective disturbances in thought, perception, and motor functioning (i.e. basic symptoms), nor regarding prodromal disorganization and general symptoms. In

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 55

Mirjam Sprong | Adolescents at risk of psychosis addition, the majority (78.1%) of MCDD adolescents unexpectedly met the ARMS criteria. However, as hypothesized, the ARMS group did report higher levels of positive and negative prodromal symptoms, and elevated scores on at least one of the positive prodromal symptoms were more common in this group. It has been suggested that in most psychotic patients, the less specific basic symptoms develop first, followed by positive, and later negative symptoms (Gross 1997). The finding that higher levels of positive and negative prodromal symptoms are reported in the ARMS group than the MCDD group, suggests that the former might be at more imminent risk of developing psychosis than the latter. This could perhaps be explained by the fact that the ARMS subjects were older. Consequently, a larger proportion falls within the age-of-onset window for psychotic disorders, which is from the late teens through early twenties for non-affective psychoses (Kessler et al. 2007). However, correlation-analysis showed that age only had an effect on SIPS Positive symptoms in the ARMS sample, although this may be an artifact of having few older MCDD subjects in the sample, or lack of power due to small sample size. The high-risk groups were not gender-matched, which is not surprising since PDDs are more prevalent in males (Volkmar et al. 2004). In our study, boys generally reported lower positive symptom levels than girls. This is in line with evidence from a study on subclinical psychotic symptoms in the general population that showed that subclinical positive symptoms are more prevalent in females (Maric et al. 2003). Post hoc analyses of only the male subjects showed that gender differences could not explain the observed results. As hypothesized, the MCDD group showed more autism traits than the ARMS group, and both high-risk groups differed from NPCs regarding schizotypal traits. Schizotypy, and particularly the positive domain, is regarded a biological-genetic vulnerability marker for psychosis (Vollema 1999). Our data support the notion suggested by Jansen et al. (2000) that such a vulnerability for psychosis may exist in subjects with MCDD. An association between PDD(-NOS) and psychosis has been reported elsewhere (e.g. Clarke et al. 1989; Mouridsen et al. 2007; Nylander and Gillberg 2001; Sporn et al. 2004; Stahlberg et al. 2004). However, whether having a PDD increases the vulnerability for psychosis, or whether the childhood developmental abnormalities that are observed in many subjects with adult schizophrenia, including social maladjustment and cognitive abnormalities (e.g. Isohanni et al. 2000; Niemi et al. 2003), are sometimes diagnosed as PDD is not clear. Some comments need to be made on the association between schizotypy and MCDD. First, when comparing SPQ-R schizotypal traits with the diagnostic criteria for MCDD, one cannot overlook the overlap regarding interpersonal (e.g. social disinterest, withdrawal, anxiety) and cognitive traits (e.g. magical thinking, delusional ideas, ideas of reference, paranoid preoccupations). Also, the diagnostic criteria for schizotypal

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 56

Mirjam Sprong | Adolescents at risk of psychosis personality disorder (American Psychiatric Association 1994) and MCDD overlap, as has also been pointed out by Cohen et al. (1986). Second, historically there has been diagnostic confusion between (childhood) schizoid and schizotypal personality disorder and PDD (Clarke et al. 1989; Parry-Jones 2001; Scheeringa 2001; Tantam 1988; Wolff 1991, 1996). It has been argued that these disorders may lie on the same continuum, or may be distinct disorders with some amount of overlap. Third, as suggested by Scheeringa (2001), schizoid and schizotypal personality disorder may be underdiagnosed in children in favor of PDD, due to negative associations with schizophrenia that clinicians may have. One might argue that the two high-risk groups in this study cannot truly be differentiated, since they did not differ regarding schizotypal traits, and because the majority of MCDD adolescents met the ARMS criteria. Also, 26.7% of the ARMS sample had a mental health contact before the age of twelve, implying that at least some of them had childhood-onset behavioral problems. This percentage is in line with the study by Corcoran et al. (2003) in which 25% of the ARMS group was reported to have early behavioral problems. However, although there may be similarities between the two high-risk samples now they are in adolescence, the data show that MCDD adolescents were much more impaired in early childhood than the ARMS adolescents. Most importantly, the MCDD subjects showed high levels of autism traits, were often unable to attend regular primary school, and in most cases started receiving mental health care before the age of six. And of course, there were no subjects with clinical diagnoses of MCDD in the ARMS group, because they would automatically be included in the MCDD group. Limitations of this study include the relatively small size of the MCDD sample causing inequality of the sample sizes, and the fact that statistical analyses were nonparametric, and thus unifactorial, because ANCOVA assumptions were not met. Furthermore, only long-term follow-up can determine whether both high-risk samples are truly at elevated risk, i.e. whether the symptoms will develop into psychosis or whether they will disappear spontaneously or after treatment. Many of our patients were already using psychopharmaceuticals. This may affect transition rates, current symptom reports, and comparability with other high-risk studies. In sum, this study contributes to the evidence for different early developmental pathways to psychosis. Future ultra high-risk research should focus on the neurocognitive similarities and differences between (diagnostic) subgroups within the “prodromal” samples, as this may lead to better insight into the pathogenesis of psychosis and the heterogeneity within the schizophrenia spectrum. In addition, longterm follow-up of these subgroups might also lead to a better distinction between true and false positives within samples that present with ARMS symptoms.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 57

Mirjam Sprong | Adolescents at risk of psychosis

References Ad-Dab'bagh,Y. and Greenfield,B., 2001. Multiple complex developmental disorder: the "multiple and complex" evolution of the "childhood borderline syndrome" construct. Journal of the American Academy of Child and Adolescent Psychiatry 40, 954-964. Addington,J., 2004. The diagnosis and assessment of individuals prodromal for schizophrenic psychosis. CNS Spectrums 9, 588-594. American Psychiatric Association, 1994. Diagnostic and statistical manual of mental disorders (4th edition). Washington DC: Author. Baker,K.D. and Skuse,D.H., 2005. Adolescents and young adults with 22q11 deletion syndrome: psychopathology in an at-risk group. The British Journal of Psychiatry 186, 115-120. Bechdolf,A., Phillips,L.J., Francey,S.M., Leicester,S., Morrison,A.P., Veith,V., Klosterkötter,J., and McGorry,P.D., 2006. Recent approaches to psychological interventions for people at risk of psychosis. European Archives of Psychiatry and Clinical Neuroscience 256, 159-173. Benvenuti,A., Rucci,P., Ravani,L., Gonnelli,C., Frank,E., Balestrieri,M., Sbrana,A., Dell'Osso,L., and Cassano,G.B., 2005. Psychotic features in borderline patients: is there a connection to mood dysregulation? Bipolar Disorders 7, 338-343. Berument,S.K., Rutter,M., Lord,C., Pickles,A., and Bailey,A., 1999. Autism screening questionnaire: diagnostic validity. The British Journal of Psychiatry 175, 444-451. Bleuler,E., 1911. Dementia praecox, or the group of schizophrenias (Translated by Zinkin,J.). New York: International Universities Press. Buitelaar,J.K. and Van der Gaag,R.J., 1998. Diagnostic rules for children with PDD-NOS and multiple complex developmental disorder. Journal of Child Psychology and Psychiatry, and Allied Disciplines 39, 911-919. Centre for Policy Related Statistics, 2007 http://www.cbs.nl. Accessed 6 June, 2007. Chong,S.A., Lee,C., Bird,L., and Verma,S., 2004. A risk reduction approach for schizophrenia: the early psychosis intervention programme. Annals of the Academy of Medicine Singapore 33, 630-635. Clarke,D.J., Littlejohns,C.S., Corbett,J.A., and Joseph,S., 1989. Pervasive developmental disorders and psychoses in adult life. The British Journal of Psychiatry 155, 692-699.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 58

Mirjam Sprong | Adolescents at risk of psychosis Cohen,D.J., Paul,R., and Volkmar,F.R., 1986. Issues in the classification of pervasive and other developmental disorders: toward DSM-IV. Journal of the American Academy of Child and Adolescent Psychiatry 25, 213-220. Cohen,D.J., Towbin,K.E., Mayes,L., and Volkmar,F., 1994. Developmental psychopathology of Multiplex Developmental Disorder. In: S.L. Friedman and H.C. Haywood (Series Ed.), Developmental follow-up: concepts, genres, domains, and methods. New York: Academic Press Inc., pp. 155-179. Cohen,J., 1988. Statistical power analysis for the behavioral sciences (2nd edition). Hillsdale NJ: Erlbaum. Corcoran,C., Davidson,L., Sills-Shahar,R., Nickou,C., Malaspina,D., Miller,T., and McGlashan,T., 2003. A qualitative research study of the evolution of symptoms in individuals identified as prodromal to psychosis. The Psychiatric Quarterly 74, 313-332. Debbane,M., Glaser,B., David,M.K., Feinstein,C., and Eliez,S., 2006. Psychotic symptoms in children and adolescents with 22q11.2 deletion syndrome: neuropsychological and behavioral implications. Schizophrenia research 84, 187-193. DeLisi,L.E., Friedrich,U., Wahlstrom,J., Boccio-Smith,A., Forsman,A., Eklund,K., and Crow,T.J., 1994. Schizophrenia and sex chromosome anomalies. Schizophrenia Bulletin 20, 495-505. Dowson,J.H., Sussams,P., Grounds,A.T., and Taylor,J., 2002. Associations of self-reported past "psychotic" phenomena with features of personality disorders. Comprehensive Psychiatry 41, 42-48. Field,A., 2005. Discovering statistics using SPSS (2nd edition). Thousand Oaks CA: SAGE Publications. Gross,G., 1997. The onset of schizophrenia. Schizophrenia Research 28, 187-198. Häfner,H., Löffler,W., Maurer,K., Hambrecht,M., and An der Heiden,W., 1999. Depression, negative symptoms, social stagnation and social decline in the early course of schizophrenia. Acta Psychiatrica Scandinavica 100, 105-118. Haroun,N., Dunn,L., Haroun,A., and Cadenhead,K.S., 2006. Risk and protection in prodromal schizophrenia: ethical implications for clinical practice and future research. Schizophrenia Bulletin 32, 166-178. Isohanni,M., Jones,P., Kemppainen,L., Croudace,T., Isohanni,I., Veijola,J., Rasanen,S., Wahlberg,K.E., Tienari,P., and Rantakallio,P., 2000. Childhood and adolescent predictors of schizophrenia in the Northern Finland 1966 birth cohort - a descriptive life-span model. European Archives of Psychiatry and Clinical Neuroscience 250, 311-319.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 59

Mirjam Sprong | Adolescents at risk of psychosis Jansen,L.M., Gispen-de Wied,C.C., Van der Gaag,R.J., Ten Hove,F., Willemsen-Swinkels,S.W., Harteveld,E., and Van Engeland,H., 2000. Unresponsiveness to psychosocial stress in a subgroup of autistic-like children, multiple complex developmental disorder. Psychoneuroendocrinology 25, 753-764. Kessler,R.C., Amminger,G.P., Aguilar-Gaxiola,S., Alonso,J., Lee,S., and Ustun,T.B., 2007. Age of onset of mental disorders: a review of recent literature. Current Opinion in Psychiatry 20, 359-364. Klosterkötter,J., Ruhrmann,S., Schultze-Lutter,F., Salokangas,R.K., Linszen,D., Birchwood,M., Juckel,G., Morrison,A., Vazquez-Barquero,J.L., Hambrecht,M., and Von Reventlow,H., 2005. The European Prediction of Psychosis Study (EPOS): integrating early recognition and intervention in Europe. World Psychiatry 4, 161-167. Kunugi,H., Lee,K.B., and Nanko,S., 1999. Cytogenetic findings in 250 schizophrenics: evidence confirming an excess of the X chromosome aneuploidies and pericentric inversion of chromosome 9. Schizophrenia Research 40, 43-47. Lord,C., Rutter,M., and Le Couteur,A., 1994. Autism Diagnostic Interview-Revised (ADI-R): a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. Journal of Autism and Developmental Disorders 24, 659-685. Maric,N., Krabbendam,L., Vollebergh,W., De Graaf,R., and Van Os,J., 2003. Sex differences in symptoms of psychosis in a non-selected, general population sample. Schizophrenia Research 63, 89-95. McGlashan, T. H., Miller, T. J, and Woods, S. W. Structured Interview for Prodromal Syndromes (SIPS) version 3.0, 2001. New Haven: PRIME Research Clinic, Yale School of Medicine. McGlashan,T.H., Zipursky,R.B., Perkins,D., Addington,J., Miller,T.J., Woods,S.W., Hawkins,K.A., Hoffman,R., Lindborg,S., Tohen,M., and Breier,A., 2003. The PRIME North America randomized doubleblind clinical trial of olanzapine versus placebo in patients at risk of being prodromally symptomatic for psychosis. I. Study rationale and design. Schizophrenia Research 61, 7-18. McGorry,P.D., Yung,A.R., Phillips,L.J., Yuen,H.P., Francey,S., Cosgrave,E.M., Germano,D., Bravin,J., McDonald,T., Blair,A., Adlard,S., and Jackson,H., 2002. Randomized controlled trial of interventions designed to reduce the risk of progression to first-episode psychosis in a clinical sample with subthreshold symptoms. Archives of General Psychiatry 59, 921-928. Miller,T.J., McGlashan,T.H., Rosen,J.L., Somjee,L., Markovich,P.J., Stein,K., and Woods,S.W., 2002. Prospective diagnosis of the initial prodrome for schizophrenia based on the Structured Interview for Prodromal Syndromes: preliminary evidence of interrater reliability and predictive validity. The American Journal of Psychiatry 159, 863-865.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 60

Mirjam Sprong | Adolescents at risk of psychosis Miller,T.J., Zipursky,R.B., Perkins,D., Addington,J., Woods,S.W., Hawkins,K.A., Hoffman,R., Preda,A., Epstein,I., Addington,D., Lindborg,S., Marquez,E., Tohen,M., Breier,A., and McGlashan,T.H., 2003. The PRIME North America randomized double-blind clinical trial of Olanzapine versus placebo in patients at risk of being prodromally symptomatic for psychosis. II. Baseline characteristics of the "prodromal" sample. Schizophrenia Research 61, 19-30. Mouridsen,S.E., Rich,B., and Isager,T., 2008. Psychiatric disorders in adults diagnosed as children with atypical autism. A case control study. Journal of Neural Transmission 115, 135-138. Murphy,K.C., Jones,L.A., and Owen,M.J., 1999. High rates of schizophrenia in adults with velo-cardiofacial syndrome. Archives of General Psychiatry 56, 940-945. Nelson,H.E., 1982. National Adult Reading Test (NART), Windsor: NFER Nelson. Niemi,L.T., Suvisaari,J.M., Tuulio-Henriksson,A., and Lonnqvist,J.K., 2003. Childhood developmental abnormalities in schizophrenia: evidence from high-risk studies. Schizophrenia Research 60, 239-258. Nylander,L. and Gillberg,C., 2001. Screening for autism spectrum disorders in adult psychiatric outpatients: a preliminary report. Acta Psychiatrica Scandinavica 103, 428-434. Parry-Jones,W.L., 2001. Childhood psychosis and schizophrenia: a historical review. In: Remschmidt,H. (ed.), Schizophrenia in children and adolescents, Cambridge: Cambridge University Press, pp. 1-23. Raine,A., 1991. The SPQ: a scale for the assessment of schizotypal personality based on DSM-III-R criteria. Schizophrenia Bulletin 17, 555-564. Raine,A., Reynolds,C., Lencz,T., Scerbo,A., Triphon,N., and Kim,D., 1994. Cognitive-perceptual, interpersonal, and disorganized features of schizotypal personality. Schizophrenia Bulletin 20, 191-201. Rodriguez Solano,J.J. and Gonzalez,D.C., 2000. Premorbid personality disorders in schizophrenia. Schizophrenia Research 44, 137-144. Rossi,A., Pollice,R., Daneluzzo,E., Marinangeli,M.G., and Stratta,P., 2000. Behavioral neurodevelopment abnormalities and schizophrenic disorder: a retrospective evaluation with the Childhood Behavior Checklist (CBCL). Schizophrenia Research 44, 121-128. Ruhrmann,S., Schultze-Lutter,F., Maier,W., and Klosterkötter,J., 2005. Pharmacological intervention in the initial prodromal phase of psychosis. European Psychiatry 20, 1-6. Scheeringa,M.S., 2001. The differential diagnosis of impaired reciprocal social interaction in children: a review of disorders. Child Psychiatry and Human Development 32, 71-89.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 61

Mirjam Sprong | Adolescents at risk of psychosis Schmael,C., Georgi,A., Krumm,B., Buerger,C., Deschner,M., Nothen,M.M., Schulze,T.G., and Rietschel,M., 2007. Premorbid adjustment in schizophrenia - an important aspect of phenotype definition. Schizophrenia Research 92, 50-62. Schmand,B., Lindeboom,J., Van Harskamp,F., 1992. Dutch adaptation of the National Adult Reading Test (NART) by Nelson, H. E. (1982): Nederlandse Leestest voor Volwassenen (NLV), Lisse: Swets & Zeitlinger. Schothorst,P.F., Emck,C., and Van Engeland,H., 2006. Characteristics of early psychosis. Comprehensive Psychiatry 47, 438-442. Schultze-Lutter,F. and Klosterkötter,J., 2002. Bonn Scale for the Assessment of Basic Symptoms Prediction list (BSABS-P). Cologne: University of Cologne. Sporn,A.L., Addington,A.M., Gogtay,N., Ordonez,A.E., Gornick,M., Clasen,L., Greenstein,D., Tossell,J.W., Gochman,P., Lenane,M., Sharp,W.S., Straub,R.E., and Rapoport,J.L., 2004. Pervasive developmental disorder and childhood-onset schizophrenia: comorbid disorder or a phenotypic variant of a very early onset illness? Biological Psychiatry 55, 989-994. Stahlberg,O., Soderstrom,H., Rastam,M., and Gillberg,C., 2004. Bipolar disorder, schizophrenia, and other psychotic disorders in adults with childhood onset AD/HD and/or autism spectrum disorders. Journal of Neural Transmission 111, 891-902. Tantam,D., 1988. Lifelong eccentricity and social isolation II: Asperger's syndrome or schizoid personality disorder? The British Journal of Psychiatry 153, 783-791. Towbin,K.E., Dykens,E.M., Pearson,G.S., and Cohen,D.J., 1993. Conceptualizing "borderline syndrome of childhood" and "childhood schizophrenia" as a developmental disorder. Journal of the American Academy of Child and Adolescent Psychiatry 32, 775-782. Van Engeland,H. and Van der Gaag,R.J., 1994. MCDD in childhood: a precursor of schizophrenic spectrum disorders. Schizophrenia Research 11, 197. Van Rijn,S., Aleman,A., Swaab,H., and Kahn,R., 2006. Klinefelter's syndrome (karyotype 47,XXY) and schizophrenia-spectrum pathology. The British Journal of Psychiatry 189, 459-460. Volkmar,F.R., Lord,C., Bailey,A., Schultz,R.T., and Klin,A., 2004. Autism and pervasive developmental disorders. Journal of Child Psychology and Psychiatry, and Allied Disciplines 45, 135-170. Vollema,M.G. and Hoijtink,H., 2000. The multidimensionality of self-report schizotypy in a psychiatric population: an analysis using multidimensional Rasch models. Schizophrenia Bulletin 26, 565-575.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 62

Mirjam Sprong | Adolescents at risk of psychosis Vollema,M.G., Sitskoorn,M.M., Appels,M.C., and Kahn,R.S., 2002. Does the Schizotypal Personality Questionnaire reflect the biological-genetic vulnerability to schizophrenia? Schizophrenia Research 54, 39-45. Vorstman,J.A., Morcus,M.E., Duijff,S.N., Klaassen,P.W., Heineman-de Boer,J.A., Beemer,F.A., Swaab,H., Kahn,R.S., and Van Engeland,H., 2006. The 22q11.2 deletion in children: high rate of autistic disorders and early onset of psychotic symptoms. Journal of the American Academy of Child and Adolescent Psychiatry 45, 1104-1113. Warreyn,P., Roeyers,H., 2001. Dutch translation of the Social Communication Questionnaire by Rutter et al. (prepublication material). Los Angeles: Western Psychological Services. Wechsler, D., 1997. Wechsler Adult Intelligence Scale-III NL: Afname en scoringshandleiding [Manual]. Psychological Corporation Ltd., Harcourt Publishers. Wechsler, D., 2002. Wechsler Intelligence Scale for Children-III NL: Handleiding en verantwoording [Manual]. Psychological Corporation Ltd., Harcourt Assessment. Wolff,S., 1991. 'Schizoid' personality in childhood and adult life I: The vagaries of diagnostic labeling. The British Journal of Psychiatry 159, 615-620. Wolff,S., 1996. The first account of the syndrome Asperger described? Translation of a paper entitled Die schizoiden Psychopathien im Kindesalter by Dr. G.E. Ssucharewa; scientific assistant, which appeared in 1926 in the Monatsschrift für Psychiatrie und Neurologie 60: 235-261. European Child and Adolescent Psychiatry 5, 119-132.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 63

Mirjam Sprong | Adolescents at risk of psychosis

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 64

Mirjam Sprong | Adolescents at risk of psychosis

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 65

Mirjam Sprong | Adolescents at risk of psychosis

Chapter 3

Neurocognitive and behavioral vulnerability markers for psychosis in adolescents at high risk: a comparison of Multiple Complex Developmental Disorder and the “At Risk Mental State”

Mirjam Sprong a, Hanna Swaab b, Hiske Becker c, Tim Ziermans a, Peter Dingemans c, Don Linszen c, Bertine Lahuis a, Herman van Engeland a, Patricia Schothorst a Submitted for publication

a

Rudolf Magnus Institute of Neuroscience/Department of Child and Adolescent Psychiatry, University Medical Center Utrecht, the Netherlands b Department of Clinical Child and Adolescent Studies, University of Leiden, the Netherlands c Department of Psychiatry, Academic Medical Center De Meren, Amsterdam, the Netherlands

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 66

Mirjam Sprong | Adolescents at risk of psychosis

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 67

Mirjam Sprong | Adolescents at risk of psychosis

Abstract Background: Neurocognitive and behavioral impairments have frequently been identified as vulnerability markers for psychosis. The hypothesis was tested that similar vulnerability markers are present in two groups, both at high risk for psychosis, but with different developmental histories, i.e. (1) adolescents with prodromal-like symptoms indicating an At Risk Mental State (ARMS), and (2) adolescents with prepubertal diagnoses of the pervasive developmental disorder subtype Multiple Complex Developmental Disorder (MCDD). In addition, associations between neurocognitive and behavioral vulnerability markers were explored. Methods: 80 ARMS adolescents, 32 MCDD adolescents, and 82 nonpsychiatric controls (NPCs), all between 12-18 years, were administered a neurocognitive test battery and a self-report questionnaire on social functioning. Results: Both high-risk groups had impairments in psychomotor speed, attentional control and verbal output generation compared to NPCs. In contrast, verbal memory, spatial working memory, cognitive flexibility, and goal setting/problem solving abilities were relatively unimpaired. Both high-risk groups reported social behavioral difficulties, and they did not differ in that respect. Social functioning was related to verbal memory and attentional control in the ARMS group, whereas no associations between neurocognitive and social functioning were observed in the MCDD group. Conclusions: Impairments of psychomotor speed, attentional control, verbal output generation, and social functioning are vulnerability markers for psychosis that are shared by at-risk adolescents with very early-onset behavioral abnormalities and at-risk adolescents with later-onset behavioral abnormalities. Follow-up into adulthood is necessary to establish the predictive validity for these vulnerability markers in the two high-risk groups.

1. Introduction Retrospective studies have shown that episodes of overt psychosis are often preceded by prodromal symptoms, such as functional decline, subtle changes in thoughts, emotions, and perceptions, and subthreshold psychotic symptoms (e.g. Häfner et al. 1999; Jackson et al. 1995; Schothorst et al. 2006). In the past decade, a growing number of research projects have been set up to identify and offer treatment to prodromal individuals, with the aim of preventing or delaying psychotic outbreak (reviewed by Addington 2004; Bechdolf et al. 2006). However, because the term ‘prodromal’ can only be used in retrospect, the terms ‘ultra high-risk’, ‘clinical high-risk’, or ‘at risk mental state’ (ARMS) are often used. Follow-up studies have shown that ARMS individuals are indeed at imminent risk of psychosis, with reported transition rates

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 68

Mirjam Sprong | Adolescents at risk of psychosis ranging from 15-54% after 6 months to 1 year (e.g. Haroun et al. 2006; Miller et al. 2002). Autism spectrum disorders have also been associated with an elevated risk of psychosis (e.g. Stahlberg et al. 2004). Recently, Mouridsen et al. (2007) reported that 34.8% of adults with childhood diagnoses of Pervasive Developmental Disorder - Not Otherwise Specified (PDD-NOS) had been diagnosed with a schizophrenia-spectrum disorder at least once in their life. A subtype of PDD-NOS that may be particularly associated with a high risk of psychosis is Multiple Complex Developmental Disorder (MCDD), which is characterized by early childhood-onset affect dysregulation, social impairment, and thought disorder (Cohen et al. 1994; Table 1). Follow-up of 55 children with MCDD revealed that 22% of the adolescents and 64% of the young adults had developed a schizophrenia-spectrum disorder (Van Engeland and Van der Gaag 1994). Furthermore, we reported earlier that 78.1% of 32 patients with childhood diagnoses of MCDD met ARMS-criteria in adolescence (Sprong et al. 2008). The fact that individuals with MCDD display severe behavioral impairments from early childhood (Cohen et al. 1994), whereas the ARMS symptoms are usually identified in adolescents and young-adults who in most cases have been relatively inconspicuous as a child (Corcoran et al. 2003), supports the notion that there are different pathways to psychosis. Additional support comes from several studies in schizophrenia patients, in which two subgroups are distinguished based on the age of onset of premorbid abnormalities such as developmental delays, scholastic underachievement, poor social adjustment, and childhood schizoid or schizotypal traits (Fuller Torrey et al. 1994; Murray et al. 1992; Neumann et al. 1995; Offord & Cross 1969; Rossi et al. 2000). Patients in the first subgroup have a markedly abnormal development from early childhood, with further escalation in adolescence or young adulthood. The other subgroup consists of patients with a relatively normal development throughout childhood, followed by behavioral changes later in life. Murray and colleagues have suggested that the first subgroup may have brain abnormalities that originate from pre- or perinatal life, higher levels of neurocognitive impairment, an earlier age of psychosis-onset, and a higher prevalence in males than the second subgroup (Murray et al. 1992; Pilowsky et al. 1993). Surprisingly, in none of the aforementioned studies the possibility is discussed that some of the individuals in the first subgroup may meet the diagnostic criteria for PDD(-NOS) in childhood. Neurocognitive and behavioral impairments have frequently been identified as vulnerability markers for psychosis. A better understanding of these vulnerability markers enhances the understanding of the pathogenesis of psychotic disorders. From a clinical perspective, it is essential for improving the identification of at-risk individuals, and for developing optimal early intervention strategies. The comparison of vulnerability markers in populations with different developmental pathways to psychosis is of

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 69

Mirjam Sprong | Adolescents at risk of psychosis particular interest, because it may lend more insight into the heterogeneity of the manifestation of the psychotic syndrome. In brief, deficits in a wide range of neurocognitive domains are reported in prepsychotic individuals (e.g. Cannon et al. 2000; Reichenberg et al. 2002; Zammit et al. 2004), and individuals at genetic risk of psychosis (Kremen et al. 1994; Sitskoorn et al. 2004; Snitz et al. 2006). ARMS individuals show impairments in verbal memory, psychomotor functioning, and executive functioning, viz. attentional control, working memory, cognitive flexibility, goal setting and problem solving, and verbal output generation, although the exact domains of impairment differ across studies (Bartok et al. 2005; Brewer et al. 2005; Eastvold et al. 2007; Francey et al. 2005; Gschwandtner et al. 2003; Hambrecht et al. 2002; Hawkins et al. 2004; Keefe et al. 2006; Lencz et al. 2006; Niendam et al. 2006, 2007a and 2007b; Pflueger et al. 2007; Pukrop et al. 2006 and 2007; Simon et al. 2007; Smith et al. 2005; Wood et al. 2003). Neurocognitive research in MCDD is scarce, but suggests that children with MCDD have impairments in some of these domains, namely executive functioning (attentional control and cognitive flexibility) and psychomotor functioning (Lincoln et al. 1998; Paris et al. 1999). A behavioral vulnerability marker for psychosis that has consistently been reported on is social maladjustment, including social anxiety and withdrawal, overly restrained behavior in social situations, but also disinhibited and antisocial behavior (Niemi et al. 2003; Olin and Mednick 1996). Recent reports indicate that ARMS individuals tend to be socially isolated and withdrawn (Lencz et al. 2004), and have impairments in interpersonal relationships, work and school (Ballon et al. 2007; Cornblatt et al. 2007). The diagnostic criteria for the PDD-NOS subtype MCDD include social disinterest, communication problems, and an inability to initiate or maintain peer relationships (American Psychiatric Association 1994; Cohen et al. 1994). As reviewed by Green et al. (2000), neurocognitive functioning is associated with social outcome in schizophrenia patients. However, the interrelationship of neurocognitive and social impairment before the onset of overt psychosis is not clear, although a correlation between social functioning and verbal memory in ARMS individuals was reported by Niendam et al. (2006). The first aim of this study is to compare neurocognitive and behavioral vulnerability markers for psychosis in two groups of adolescents, both at high risk of developing a first psychotic episode, but with different developmental histories, i.e. (a) help-seeking adolescents with signs and symptoms indicating an ARMS, and (b) adolescents with prepubertal diagnoses of MCDD. We specifically focus on established neurocognitive vulnerability markers for psychosis, i.e. (1) verbal memory, (2) psychomotor functioning, and (3) various subdomains of executive functioning. We hypothesize that the two highrisk groups will show similar neurocognitive impairments compared to nonpsychiatric controls. In addition, both high-risk groups are hypothesized to have social impairments.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 70

Mirjam Sprong | Adolescents at risk of psychosis Since the MCDD group is defined by the presence of disturbed social behavior and the ARMS group is not, higher levels of social impairment are expected in the former than in the latter. The second aim is to explore the interrelationships of neurocognitive and social impairments in these high-risk adolescents. Based on the study by Niendam et al. (2006), we expected a positive association in both high-risk groups, in particular for verbal memory.

2. Methods This study is part of the Dutch Prediction of Psychosis Study, a cooperation between the University Medical Center (UMC) in Utrecht, and the Psychiatric Clinic for Adolescents of the Academic Medical Center (AMC) in Amsterdam. The Amsterdam site participates in the European Prediction of Psychosis Study (EPOS; Klosterkötter et al. 2005).

2.1. Subjects The ARMS sample consisted of 80 help-seeking adolescents (n = 46 UMC, n = 34 AMC) who met at least one of the ARMS criteria as defined within EPOS, i.e. having (1) attenuated positive symptoms, (2) brief or intermittent psychotic symptoms with a total duration of ≤ one week, (3) a 30% reduction in level of social, occupational/school-, and psychological functioning in the past year, combined with a genetic risk of psychosis, or (4) two or more of a selection of nine ‘basic symptoms’, i.e. subjective deficits in cognitive, perceptual, or motor functioning. The first three criteria were assessed with the Structured Interview for Prodromal Syndromes (SIPS; McGlashan et al. 2001), which includes a Global Assessment of Functioning (GAF) scale. The fourth criterion was assessed with the Bonn Scale for the Assessment of Basic Symptoms-Prediction List (BSABS-P; Schultze-Lutter and Klosterkötter 2002). The MCDD sample consisted of 32 adolescents with prepubertal DSM-IV diagnoses of PDD-NOS (American Psychiatric Association 1994), who additionally met the diagnostic criteria for MCDD (Cohen et al. 1994; Table 1). Diagnoses were confirmed by expert clinical opinion (HvE, PS, BL) after psychiatric examination including the Autism Diagnostic Interview-Revised (Lord et al. 1994), as well as a parent-interview based on the MCDD criteria (Cohen et al. 1994), which was developed for internal use at the UMC. Consecutively, the MCDD criteria were rated using the information present in the medical records (MS, PS, BL).

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 71

Mirjam Sprong | Adolescents at risk of psychosis

82 nonpsychiatric controls (NPCs) were recruited from secondary schools in the region of Utrecht. They were excluded if they met one or more of the ARMS criteria, or if they had a history of any psychiatric illness themselves or in a first degree relative, or a second degree relative with a psychotic disorder. All participants were aged between 12-18 years, and all had a verbal IQ (VIQ) ≥ 75. At the UMC, VIQ was assessed with the Wechsler Intelligence Scales (1997 and 2002), of which the standardized score based on age-related samples was used. At the AMC, VIQ was estimated using the Dutch version of the National Adult Reading Test (NART; Nelson

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 72

Mirjam Sprong | Adolescents at risk of psychosis 1982; Schmand et al. 1992). None of the participants had ever experienced a psychotic episode lasting more than one week, defined as the presence of positive symptoms that are seriously disorganizing (McGlashan et al. 2001). Additional information on the patients, including information on treatment and family history, and childhood behavioral adjustment, was collected in a parent-interview.

2.2. Neurocognitive vulnerability markers 2.2.1. Verbal memory Verbal memory was assessed with the Dutch 15-Words Task (15WT; Saan & Deelman 1986) that was based on Rey’s Auditory Verbal Learning Test (Rey 1964). Participants were asked to recall a list of 15 auditorily presented, unrelated one-syllable words, which was repeated over five trials. After a delay of 20 minutes, they were requested to recall the words from memory. Dependent variables were. a. total acquisition, i.e. the total score of free recall of the five trials (max. 75), and b. retention, i.e. the number of words remembered after the delay (max. 15). Only UMC data were used in the analyses, because in the AMC a verbal memory task was used that is incompatible with the 15WT.

2.2.2. Psychomotor functioning A computer-administered finger tapping test (FTT) was used to assess psychomotor speed (Rombouts 2002a). Participants were asked to tap their index finger onto a mouse button as often as possible for 10 seconds. The mean number of dominant hand finger tappings of five trials was used in the analyses.

2.2.3. Executive functioning The developmental model of executive functioning (EF) according to Anderson (2002) was used to define and classify EF. This model incorporates four interrelated domains that together enable executive control: a. attentional control, i.e. the capacity to selectively attend to specific stimuli, focus attention for a prolonged period, and inhibit prepotent responses, b. working memory and cognitive flexibility, i.e. the ability to divide attention, process multiple sources of information concurrently, learn from mistakes, and devise alternative strategies, c. goal setting and problem solving, i.e. the ability to develop new initiatives and concepts, plan actions in advance, and approach tasks in an efficient and strategic manner, and d. output generation (or information processing as it was labeled by Anderson, 2002), i.e. the speed, quality and quantity of output generation. a. Attentional control To measure sustained attention, the no distraction-fast condition of the computer-

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 73

Mirjam Sprong | Adolescents at risk of psychosis administered Continuous Performance Test-Identical Pairs version 2.0 (CPT-IP; Cornblatt 2000) was selected. Participants were asked to respond as quickly as possible whenever two identical visual stimuli were presented in a row (fixed stimulus interval 950 ms, fixed stimulus duration 50 ms). In the first condition stimuli were four-digit numbers, and in the second condition stimuli were nonsense shapes, which are considered to be verbal and nonverbal stimuli respectively. Both conditions consisted of 150 trials. The CPT-IP has been described as demanding of both attention and working memory capacity, because each stimulus must first be processed, and then held in memory until it can be compared with the next stimulus to determine whether there is an exact match (Cornblatt 2000). Dependent variables were % hits and the sensitivity index d’, averaged over the two conditions. The latter is computed from hits and false alarms and measures the ability to discriminate a signal from background noise. b. Working memory and cognitive flexibility Working memory was assessed with the computer-administered Spatial Working Memory Test (SWMT; Rombouts 2002b), which requires remembering the spatial location of a visual stimulus over a brief delay. In the first condition, participants were asked to click with the cursor on the location of the stimulus on the computer screen immediately after it had disappeared. In the second condition, there was a distraction interval of 30 seconds between stimulus disappearance and response. Since manipulation of the stimulus information was not required in either condition, the SWMT only assessed the short-term memory component of the working memory construct. Dependent variables were the mean distances between target and response in number of pixels (transformed to a 640 x 480 pixel standard screen) for the two conditions separately. The number of perseverative errors on a computerized variation of the Wisconsin Card Sorting Test was used as a measure of cognitive flexibility (CST; Rombouts 2002c). Because at the AMC site another version of the CST was used, only UMC data were used in the analyses. c. Goal setting and problem solving The number of series completed on the CST (Rombouts 2002c) was used as a measure of problem solving ability and the ability to develop new concepts. d. Output generation A verbal fluency (VF) test was used to assess the quality and quantity of verbal output generation. Participants were first asked to name as many words as possible with the initial letter ‘S’ within one minute. Thereafter, they were asked to name words from the semantic category ‘animals’. Dependent variable for this task was the mean number of

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 74

Mirjam Sprong | Adolescents at risk of psychosis acceptable words produced, averaged over both conditions.

2.3. Behavioral vulnerability markers To measure social functioning, four scales of the self-report Child Health Questionnaire Child-Form 87 (Landgraf et al. 1999) were selected, i.e. a. Role/social-emotional, assessing limitations in schoolwork and activities with friends due to emotional difficulties, b. Role/social-behavioral, assessing limitations in schoolwork and activities with friends due to behavioral difficulties, c. Self esteem, assessing satisfaction with school and athletic ability, looks/appearance, ability to get along with others and family, and life overall, and d. General behavior, assessing overt behavior problems and ability to get along with others. Each scale score ranges from 0-100, with a higher score indicating better functioning.

2.4. Data analysis Data distributions were checked for normality and homogeneity of the variances. In case ANOVA assumptions were not met, nonparametric tests were used. Alpha was set at .05, and although some of the a priori hypotheses were directional, the more conservative two-tailed probability levels were used, except in the more exploratory correlation analyses where one-tailed probability levels were used to allow for the recognition of smaller effects to generate hypotheses for future research. Effect sizes Pearson’s r were calculated and then rated following the widely used convention for appraising effect sizes in the behavioral sciences: r = .10 was considered a small effect, r = .30 a medium effect, and r = .50 a large effect (Cohen 1988). Group differences in gender and age were revealed by χ2 -tests and ANOVA. Subsequently, group differences in neurocognitive functioning were tested by ANCOVA controlling for gender and age, with planned contrasts of the high-risk groups versus the NPCs. Because of the skewed data-distributions of the four social functioning scales, group differences were analyzed by Kruskal-Wallis tests, with post hoc Bonferroni-corrected Mann-Whitney tests on all possible comparisons. Possible confounding effects of age and gender on social functioning were explored by non-parametric correlation analyses. Finally, the partial correlations (rXY.gender,age) between the total score of the four social functioning scales (SFtot) and verbal memory and the neurocognitive measures that significantly differentiated the high-risk samples from the NPCs were tested. SFtot data were normally distributed in both high-risk samples.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 75

Mirjam Sprong | Adolescents at risk of psychosis

3. Results 3.1. Subjects As described in an earlier report, there were significant group differences in age, sex ratio and VIQ (Sprong et al. 2008; Table 2). Of the ARMS sample 43.8% met one, 45.0% met two, and 11.3% met three of the four inclusion criteria for ARMS. The MCDD sample met a mean number of 8.5 (SD = 2.6) MCDD criteria, and 78.1% also met at least one of the ARMS criteria, despite the fact that these were not part of the inclusion criteria for the MCDD group. The MCDD adolescents had more severe early childhood-onset behavioral problems than the ARMS adolescents, exemplified by a larger proportion of MCDD adolescents with a first mental health contact before age six. Also, many of the MCDD adolescents had received special primary education, whereas the proportion of ARMS adolescents who had received special primary education compared well with the general Dutch population (Centre for Policy Related Statistics 2007). Figure 1. Neurocognitive performance in two groups of adolescents at high risk for psychosis (M z-scores relative to a nonpsychiatric control group, adjusted for age and gender ± SE)

Note. ARMS = At Risk Mental State; MCDD = Multiple Complex Developmental Disorder Verbal memory: 15 Words Task (average of acquisition and retention) Psychomotor functioning: Finger Tapping Test Attentional control: Continuous Performance Test - Identical Pairs (average of % hits and d’) Working memory: Spatial Working Memory Test (average of condition 1 and condition 2) Cognitive flexibility: Modified Card Sorting Test - perseverations Goal setting/problem solving: Modified Card Sorting - number of series completed Output generation: Verbal Fluency Test

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 76

Mirjam Sprong | Adolescents at risk of psychosis

3.2. Neurocognitive assessment The neurocognitive performance of the high-risk groups is displayed as mean adjusted z-values, based on the means and standard deviations of the NPCs (Figure 1). Where applicable z-values were reversed so that negative values always reflected poorer performance, and multiple z-scores within one domain were averaged to obtain a single z-score for each domain. Statistical analyses revealed that both high-risk groups significantly differed from NPCs in psychomotor functioning, attentional control, and output generation, with small to medium effect sizes (Table 3). Post hoc analysis showed that the MCDD sample had a significantly lower psychomotor speed than the ARMS sample (F(1,97) = 7.13, p = .009). There were no group differences in verbal memory, working memory, cognitive flexibility, and goal setting/problem solving abilities.

3.3. Social functioning The high-risk groups scored lower than the NPCs on all four social functioning scales, representing medium to large effect sizes (Table 4). There were no differences between the high-risk groups. Confounder analyses revealed a significant correlation between Role/social-behavioral scores and gender in the MCDD sample (τ = .404, p = .019), with girls (Mdn = 72) scoring lower than boys (Mdn = 100), U = 28.00, p = .018. However, rerunning the ANCOVA on only the data for the male high-risk subjects did not change the conclusions.

3.4. Interrelationships between neurocognitive and behavioral vulnerability markers In the ARMS group, social functioning (SFtot) was related to verbal memory retention (15WT direct recall: r = .299, p = .032) and attentional control (CPT-IP % hits: r = .324, p = .022), but not to verbal intellectual abilities, psychomotor speed, and verbal output generation. In the MCDD group, SFtot was not related to any of the neurocognitive measures.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 77

Mirjam Sprong | Adolescents at risk of psychosis

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 78

Mirjam Sprong | Adolescents at risk of psychosis

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 79

Mirjam Sprong | Adolescents at risk of psychosis

4. Discussion The general aim of this study was to compare neurocognitive and behavioral vulnerability markers for psychosis in two groups of adolescents, both at high-risk of developing a first psychotic episode but with different developmental histories, i.e. adolescents with ‘prodromal-like’ symptoms indicating an ARMS, and adolescents with prepubertal diagnoses of the MCDD subtype of PDD-NOS. In line with the first hypothesis, the high-risk groups showed similar deficits in psychomotor speed, and some of the executive functions (i.e. attentional control and verbal output generation). Contrary to expectations, no deficits were observed for verbal memory and other executive functions (i.e. spatial working memory, cognitive flexibility, and goal setting/problem solving). In line with the second hypothesis, both high-risk groups reported social behavioral difficulties, but they unexpectedly did not differ in that respect. Regarding the third hypothesis, some associations between neurocognitive and social functioning were observed in the ARMS group, but not in the MCDD group. The neurocognitive findings for the MCDD group are not corroborated by the literature. Firstly, Lincoln et al. (1998) reported impaired motor dexterity but unimpaired motor speed in children with Borderline Disorder/MCDD and comorbid Attention Deficit/Hyperactivity Disorder. These children further showed impaired cognitive

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 80

Mirjam Sprong | Adolescents at risk of psychosis flexibility, but no attentional problems. However, because of differences in operationalization, the results are hardly comparable to our results. Secondly, Paris et al. (1999) described impairments of attention, cognitive flexibility and goal setting/problem solving in children with borderline pathology, which was considered to be similar to MCDD. Unfortunately, the diagnostic criteria for borderline pathology were not reported, rendering it unclear how well they compare with Cohen et al.’s criteria for MCDD. Thus, the empirical evidence for neurocognitive deficits in MCDD is limited and heterogeneous, and in need of replication. The neurocognitive findings for the ARMS group are largely in line with those of other studies (psychomotor functioning: Gschwandtner et al. 2003; Niendam et al. 2006 and 2007a; sustained attention as measured with the CPT-IP: Francey et al. 2005; Hambrecht et al. 2002; Hawkins et al. 2004; Lencz et al. 2006; Pukrop et al. 2006; verbal output generation: Hambrecht et al. 2002; Hawkins et al. 2004; Keefe et al. 2006; Pukrop et al. 2006 and 2007; Simon et al. 2007). However, negative findings have been reported in other studies (psychomotor functioning: Keefe et al. 2006; sustained attention as measured with the CPT-IP: Keefe et al. 2006; Pukrop et al. 2007; verbal output generation: Brewer et al. 2005). In the present study, the ARMS group showed no impairments in verbal memory, spatial working memory, cognitive flexibility, and goal setting/problem solving. Eight studies have assessed spatial working memory in ARMS individuals, of which five did not (Hambrecht et al. 2002; Hawkins et al. 2004; Keefe et al. 2006; Pukrop et al. 2006 and 2007), and three did report impairment (Bartok et al. 2005; Smith et al. 2005; Wood et al. 2003). In the study by Hawkins et al. (2004), ARMS individuals even had an better spatial working memory performance. Similarly, some researchers did not find executive functioning impairment using a type of card sorting test (Eastvold et al. 2007; Hambrecht et al. 2002; Pukrop et al. 2006 and 2007), while others did (Gschwandtner et al. 2003; Pflueger et al. 2007; Simon et al. 2007). Unfortunately, comparability of the studies is severely compromised by multiple sources of heterogeneity, including differences in definitions of ARMS and other sample characteristics, operationalization of the neurocognitive domains, sample sizes affecting statistical power, and whether or not confounder corrections have been applied. One of the most obvious study effects that may explain why the ARMS adolescents in the present study did not show significant impairments in most of the neurocognitive variables is the fact that our patients were relatively young in comparison with most other studies. Neurocognitive functioning of ARMS individuals has been reported to be at intermediate levels between nonpsychiatric controls and first-episode groups (Eastvold et al. 2007; Keefe et al. 2006; Pukrop et al. 2006; Simon et al. 2007), suggesting a decline closer to the onset of psychosis. Because our patients were relatively young, and thus further from the age window in which first psychotic episodes commonly occur (Kessler et al. 2007), our study may not be fully comparable to other

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 81

Mirjam Sprong | Adolescents at risk of psychosis studies in terms of premorbid neurocognitive decline. Speculatively, the finding that the MCDD group did not report lower levels of social functioning than the ARMS group may be explained by the fact that a self-report and thus subjective measure of social functioning was used. Possibly the loss of social abilities in ARMS patients feels worse than the innate lack of these abilities that is pathognomonic of MCDD. Also, because adolescents with MCDD have social impairments from early childhood, the system (e.g. family, special schools) will be better accommodated to these impairments, which in turn may affect the experienced level of social functioning of these adolescents. In line with the reported findings by Niendam et al. (2006), social functioning was found to be related to verbal memory in the ARMS group. Additionally, social functioning was related to attentional control, a domain that was not assessed in that study. The absence of significant associations between neurocognitive and behavioral functioning in the MCDD group may be explained by the above mentioned potential problems associated with the use of a self-report measure of social functioning. Another possibility is that the mechanisms for the interrelationship between social and cognitive functioning differ between the two high-risk groups. The early onset of MCDD is suggestive of an earlyonset brain disorder. According to developmental neuropsychologists, the earlier the brain insult, the greater the likelihood of global impairment (Anderson et al. 2001). Thus, individuals with MCDD may have more global neurocognitive and behavioral impairments, leading to more complex interrelationships. Childhood-onset problems leading to a mental health contact before the age of 12 were present in 26.7% of the ARMS adolescents. This proportion is comparable to that in the study by Corcoran et al. (2003), in which 25% of the ARMS group had early-onset problems. One might argue that this ‘early-onset’ ARMS subgroup cannot truly be differentiated from the MCDD sample, even more so because the majority of MCDD adolescents (78.1%) met ARMS criteria. However, the data show that the MCDD group was much more behaviorally impaired in early childhood, even in comparison with the ‘early-onset’ ARMS subgroup. The MCDD adolescents were often unable to attend regular primary school, and in most cases already started receiving mental health care before the age of six. Most importantly, there were no individuals with MCDD diagnoses in the ARMS sample, because they would automatically have been included in the MCDD sample. Of course, the classification of early development as either normal or abnormal is arbitrary. Behavioral abnormalities, and possibly even the underlying brain abnormalities, are perhaps better represented as a continuum rather than as two distinct categories. Some limitations of this study should be mentioned. Firstly, the mean VIQ of the NPCs was above the level of the standardized mean (= 100) suggesting that there may have been a selection bias towards more intellectually gifted NPCs. However, because all

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 82

Mirjam Sprong | Adolescents at risk of psychosis participants with a VIQ below 75 were excluded from the study, and because lower VIQs may be more prevalent in psychiatric patients, there may also have been an upward selection bias in the high-risk samples. The effects of these potential biases are unclear. Secondly, the use of psychopharmaceuticals was not an exclusion criterion for the highrisk groups, possibly affecting neurocognitive and social functioning, as well as comparability with other ARMS studies. Thirdly, long-term follow-up of both high-risk samples is needed to reveal who will make a transition to psychosis, and therefore can truly be considered to be in a prodromal phase of psychosis. It is likely that high-risk individuals that do make a transition to psychosis show higher levels of neurocognitive and social impairment. Fourthly, these data cannot answer questions whether the timing of the onset of the impairments, and the neurological bases of these impairments differ in the two high-risk groups. In sum, impairments of psychomotor speed, attentional control, verbal output generation, and social functioning are potential vulnerability markers for psychosis. It is striking that these impairments are shared by high-risk adolescents with very early-onset behavioral abnormalities and high-risk adolescents with late(r)-onset behavioral abnormalities. Follow-up into adulthood is necessary to establish the predictive validity of these impairments for transition to psychosis in the two high-risk groups. Future research should focus on the relationship between brain structure and functioning in high-risk groups with different developmental histories, and address the question whether the observed deficits are specific vulnerability markers for psychosis or whether they represent a vulnerability to psychopathology in general.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 83

Mirjam Sprong | Adolescents at risk of psychosis

References Addington,J., 2004. The diagnosis and assessment of individuals prodromal for schizophrenic psychosis. CNS Spectrums 9, 588-594. American Psychiatric Association, 1994. Diagnostic and statistical manual of mental disorders (4th edition). Washington DC: Author. Anderson,P., 2002. Assessment and development of executive functioning (EF) during childhood. Child Neuropsychology 8, 71-82. Anderson,V., Northam,E., Hendy,J., and Wrennal,J., 2001. Developmental neuropsychology: a clinical approach. East Sussex: Psychology Press Ltd. Ballon,J.S., Kaur,T., Marks,I.I., and Cadenhead,K.S., 2007. Social functioning in young people at risk for schizophrenia. Psychiatry Research 151, 29-35. Bartók,E., Berecz,R., Glaub,T., and Degrell,I., 2005. Cognitive functions in prepsychotic patients. Progress in Neuropsychopharmacology and Biological Psychiatry 29, 621-625. Bechdolf,A., Phillips,L.J., Francey,S.M., Leicester,S., Morrison,A.P., Veith,V., Klosterkötter,J., and McGorry,P.D., 2006. Recent approaches to psychological interventions for people at risk of psychosis. European Archives of Psychiatry and Clinical Neuroscience 256, 159-173. Brewer,W.J., Francey,S.M., Wood,S.J., Jackson,H.J., Pantelis,C., Phillips,L.J., Yung,A.R., Anderson,V.A., and McGorry,P.D., 2005. Memory impairments identified in people at ultra-high risk for psychosis who later develop first-episode psychosis. The American Journal of Psychiatry 162, 71-78. Cannon,T.D., Bearden,C.E., Hollister,J.M., Rosso,I.M., Sanchez,L.E., and Hadley,T., 2000. Childhood cognitive functioning in schizophrenia patients and their unaffected siblings: a prospective cohort study. Schizophrenia Bulletin 26, 379-393. Centre for Policy Related Statistics, 2007 http://www.cbs.nl. Accessed 6 June, 2007. Cohen,D.J., Paul,R., and Volkmar,F.R., 1986. Issues in the classification of pervasive and other developmental disorders: toward DSM-IV. Journal of the American Academy of Child and Adolescent Psychiatry 25, 213-220. Cohen,D.J., Towbin,K.E., Mayes,L., and Volkmar,F., 1994. Developmental psychopathology of Multiplex Developmental Disorder. In: S.L. Friedman and H.C. Haywood (Series Ed.), Developmental follow-up: concepts, genres, domains, and methods. New York: Academic Press Inc., pp. 155-179.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 84

Mirjam Sprong | Adolescents at risk of psychosis Cohen,J., 1988. Statistical power analysis for the behavioral sciences (2nd edition). Hillsdale NJ: Erlbaum. Corcoran,C., Davidson,L., Sills-Shahar,R., Nickou,C., Malaspina,D., Miller,T., and McGlashan,T., 2003. A qualitative research study of the evolution of symptoms in individuals identified as prodromal to psychosis. The Psychiatric Quarterly 74, 313-332. Cornblatt,B.A., 2000. Continuous Performance Test-Identical Pairs version, release 2.0 [Computer software] New York: Author. Cornblatt,B.A., Auther,A.M., Niendam,T., Smith,C.W., Zinberg,J., Bearden,C.E., and Cannon,T.D., 2007. Preliminary findings for two new measures of social and role functioning in the prodromal phase of schizophrenia. Schizophrenia Bulletin 33, 688-702. Eastvold,A.D., Heaton,R.K., and Cadenhead,K.S., 2007. Neurocognitive deficits in the (putative) prodrome and first episode of psychosis. Schizophrenia Research 93, 266-277. Francey,S.M., Jackson,H.J., Phillips,L.J., Wood,S.J., Yung,A.R., and McGorry,P.D., 2005. Sustained attention in young people at high risk of psychosis does not predict transition to psychosis. Schizophrenia Research 79, 127-136. Fuller Torrey,E., Bowler,A.E., Taylor,E.H., and Gottesman,I.I., 1994. Schizophrenia and manic-depressive disorder. The biological roots of mental illness as revealed by the landmark study of identical twins. New York: BasicBooks. Green,M.F., Kern,R.S., Braff,D.L., and Mintz,J., 2000. Neurocognitive deficits and functional outcome in schizophrenia: are we measuring the "right stuff"? Schizophrenia Bulletin 26, 119-136. Gschwandtner,U., Aston,J., Borgwardt,S., Drewe,M., Feinendegen,C., Lacher,D., Lanzarone,A., Stieglitz,R.D., and Riecher-Rössler,A., 2003. Neuropsychological and neurophysiological findings in individuals suspected to be at risk for schizophrenia: preliminary results from the Basel early detection of psychosis study. Acta Psychiatrica Scandinavica 108, 152-155. Häfner,H., Löffler,W., Maurer,K., Hambrecht,M., and An der Heiden,W., 1999. Depression, negative symptoms, social stagnation and social decline in the early course of schizophrenia. Acta Psychiatrica Scandinavica 100, 105-118. Hambrecht,M., Lammertink,M., Klosterkötter,J., Matuschek,E., and Pukrop,R., 2002. Subjective and objective neuropsychological abnormalities in a psychosis prodrome clinic. The British Journal of Psychiatry 181, S30-S37.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 85

Mirjam Sprong | Adolescents at risk of psychosis Haroun,N., Dunn,L., Haroun,A., and Cadenhead,K.S., 2006. Risk and protection in prodromal schizophrenia: ethical implications for clinical practice and future research. Schizophrenia Bulletin 32, 166-178. Hawkins,K.A., Addington,J., Keefe,R.S., Christensen,B., Perkins,D.O., Zipurksy,R., Woods,S.W., Miller,T.J., Marquez,E., Breier,A., and McGlashan,T.H., 2004. Neuropsychological status of subjects at high risk for a first episode of psychosis. Schizophrenia Research 67, 115-122. Jackson,H.J., McGorry,P.D., and Dudgeon,P., 1995. Prodromal symptoms of schizophrenia in first-episode psychosis: prevalence and specificity. Comprehensive Psychiatry 36, 241-250. Keefe,R.S., Perkins,D.O., Gu,H., Zipursky,R.B., Christensen,B.K., and Lieberman,J.A., 2006. A longitudinal study of neurocognitive function in individuals at-risk for psychosis. Schizophrenia Research 88, 26-35. Kessler,R.C., Amminger,G.P., Aguilar-Gaxiola,S., Alonso,J., Lee,S., and Ustun,T.B., 2007. Age of onset of mental disorders: a review of recent literature. Current Opinion in Psychiatry 20, 359-364. Klosterkötter,J., Ruhrmann,S., Schultze-Lutter,F., Salokangas,R.K., Linszen,D., Birchwood,M., Juckel,G., Morrison,A., Vazquez-Barquero,J.L., Hambrecht,M., and Von Reventlow,H., 2005. The European Prediction of Psychosis Study (EPOS): integrating early recognition and intervention in Europe. World Psychiatry 4, 161-167. Kremen,W.S., Seidman,L.J., Pepple,J.R., Lyons,M.J., Tsuang,M.T., and Faraone,S.V., 1994. Neuropsychological risk indicators for schizophrenia: a review of family studies. Schizophrenia Bulletin 20, 103-119. Landgraf,J.M., Abetz,L., and Ware,J.E., 1999. Child Health Questionnaire (CHQ): a user's manual. Boston MA: HealthAct. Lencz,T., Smith,C.W., Auther,A., Correll,C.U., and Cornblatt,B., 2004. Nonspecific and attenuated negative symptoms in patients at clinical high-risk for schizophrenia. Schizophrenia Research 68, 37-48. Lencz,T., Smith,C.W., McLaughlin,D., Auther,A., Nakayama,E., Hovey,L., and Cornblatt,B.A., 2006. Generalized and specific neurocognitive deficits in prodromal schizophrenia. Biological Psychiatry 59, 863-871. Lincoln,A.J., Bloom,D., Katz,M., and Boksenbaum,N., 1998. Neuropsychological and neurophysiological indices of auditory processing impairment in children with multiple complex developmental disorder. Journal of the American Academy of Child and Adolescent Psychiatry 37, 100-112.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 86

Mirjam Sprong | Adolescents at risk of psychosis Lord,C., Rutter,M., and Le Couteur,A., 1994. Autism Diagnostic Interview-Revised (ADI-R): a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. Journal of Autism and Developmental Disorders 24, 659-685. McGlashan, T. H., Miller, T. J, and Woods, S. W. Structured Interview for Prodromal Syndromes (SIPS) version 3.0, 2001. New Haven: PRIME Research Clinic, Yale School of Medicine. Miller,T.J., McGlashan,T.H., Rosen,J.L., Somjee,L., Markovich,P.J., Stein,K., and Woods,S.W., 2002. Prospective diagnosis of the initial prodrome for schizophrenia based on the Structured Interview for Prodromal Syndromes: preliminary evidence of interrater reliability and predictive validity. The American Journal of Psychiatry 159, 863-865. Mouridsen,S.E., Rich,B., and Isager,T., 2008. Psychiatric disorders in adults diagnosed as children with atypical autism. A case control study. Journal of Neural Transmission 115, 135-138. Murray,R.M., O'Callaghan,E., Castle,D.J., and Lewis,S.W., 1992. A neurodevelopmental approach to the classification of schizophrenia. Schizophrenia Bulletin 18, 319-332. Nelson,H.E., 1982. National Adult Reading Test (NART), Windsor: NFER Nelson. Neumann,C.S., Grimes,K., Walker,E.F., and Baum,K., 1995. Developmental pathways to schizophrenia: behavioral subtypes. Journal of Abnormal Psychology 104, 558-566. Niemi,L.T., Suvisaari,J.M., Tuulio-Henriksson,A., and Lonnqvist,J.K., 2003. Childhood developmental abnormalities in schizophrenia: evidence from high-risk studies. Schizophrenia Research 60, 239-258. Niendam,T.A., Bearden,C.E., Johnson,J.K., McKinley,M., Loewy,R., O'Brien,M., Nuechterlein,K.H., Green,M.F., and Cannon,T.D., 2006. Neurocognitive performance and functional disability in the psychosis prodrome. Schizophrenia Research 84, 100-111. Niendam,T.A., Bearden,C.E., Zinberg,J., Johnson,J.K., O'brien,M., and Cannon,T.D., 2007a. The course of neurocognition and social functioning in individuals at ultra high risk for psychosis. Schizophrenia Bulletin 33, 772-781. Niendam,T.A., Horwitz,J., Bearden,C.E., and Cannon,T.D., 2007b. Ecological assessment of executive dysfunction in the psychosis prodrome: a pilot study. Schizophrenia Research 93, 350-354. Offord,D.R. and Cross,L.A., 1969. Behavioral antecedents of adult schizophrenia: a review. Archives of General Psychiatry 21, 267-283. Olin,S.C. and Mednick,S.A., 1996. Risk factors of psychosis: identifying vulnerable populations premorbidly. Schizophrenia Bulletin 22, 223-240.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 87

Mirjam Sprong | Adolescents at risk of psychosis Paris,J., Zelkowitz,P., Guzder,J., Joseph,S., and Feldman,R., 1999. Neuropsychological factors associated with borderline pathology in children. Journal of the American Academy of Child and Adolescent Psychiatry 38, 770-774. Pflueger,M.O., Gschwandtner,U., Stieglitz,R.D., and Riecher-Rossler,A., 2007. Neuropsychological deficits in individuals with an at risk mental state for psychosis - Working memory as a potential trait marker. Schizophrenia Research 97, 14-24. Pilowsky,L.S., Kerwin,R.W., and Murray,R.M., 1993. Schizophrenia: a neurodevelopmental perspective. Neuropsychopharmacology 9, 83-91. Pukrop,R., Ruhrmann,S., Schultze-Lutter,F., Bechdolf,A., Brockhaus-Dumke,A., and Klosterkötter,J., 2007. Neurocognitive indicators for a conversion to psychosis: comparison of patients in a potentially initial prodromal state who did or did not convert to a psychosis. Schizophrenia Research 92, 116-125. Pukrop,R.,

Schultze-Lutter,F.,

Ruhrmann,S.,

Brockhaus-Dumke,A.,

Tendolkar,I.,

Bechdolf,A.,

Matuschek,E., and Klosterkötter,J., 2006. Neurocognitive functioning in subjects at risk for a first episode of psychosis compared with first- and multiple-episode schizophrenia. Journal of Clinical and Experimental Neuropsychology 28, 1388-1407. Reichenberg,A., Weiser,M., Rabinowitz,J., Caspi,A., Schmeidler,J., Mark,M., Kaplan,Z., and Davidson,M., 2002. A population-based cohort study of premorbid intellectual, language, and behavioral functioning in patients with schizophrenia, schizoaffective disorder, and nonpsychotic bipolar disorder. The American Journal of Psychiatry 159, 2027-2035. Rey,A., 1964. L'examen clinique en psychologie. Paris: Presses Universitaires de France. Rombouts, R.P., 2002a. Finger Tapping Test, CDLJava [Computer software]. Lelystad: BuroTesteR. Rombouts, R.P., 2002b. Spatial Working Memory Test, CDLJava [Computer software]. Lelystad: BuroTesteR. Rombouts, R.P., 2002c. Card Sorting Test, CDLJava [Computer software]. Lelystad: BuroTesteR. Rossi,A., Pollice,R., Daneluzzo,E., Marinangeli,M.G., and Stratta,P., 2000. Behavioral neurodevelopment abnormalities and schizophrenic disorder: a retrospective evaluation with the Childhood Behavior Checklist (CBCL). Schizophrenia Research 44, 121-128. Saan,R.J., Deelman,B.G., 1986. De 15 Woordentaak A en B [15 Words task]. Groningen: Department of Neuropsychology, Academic Hospital Groningen.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 88

Mirjam Sprong | Adolescents at risk of psychosis Schmand,B., Lindeboom,J., Van Harskamp,F., 1992. Dutch adaptation of the National Adult Reading Test (NART) by Nelson, H. E. (1982): Nederlandse Leestest voor Volwassenen (NLV), Lisse: Swets & Zeitlinger. Schothorst,P.F., Emck,C., and Van Engeland,H., 2006. Characteristics of early psychosis. Comprehensive Psychiatry 47, 438-442. Schultze-Lutter,F. and Klosterkötter,J., 2002. Bonn Scale for the Assessment of Basic Symptoms Prediction list (BSABS-P). Cologne: University of Cologne. Simon,A.E., Cattapan-Ludewig,K., Zmilacher,S., Arbach,D., Gruber,K., Dvorsky,D.N., Roth,B., Isler,E., Zimmer,A., and Umbricht,D., 2007. Cognitive functioning in the schizophrenia prodrome. Schizophrenia Bulletin 33, 761-771. Sitskoorn,M.M., Aleman,A., Ebisch,S.J., Appels,M.C., and Kahn,R.S., 2004. Cognitive deficits in relatives of patients with schizophrenia: a meta-analysis. Schizophrenia Research 71, 285-295. Smith,C.W., Park,S., and Cornblatt,B., 2005. Spatial working memory deficits in adolescents at clinical high risk for schizophrenia. Schizophrenia Research 81, 211-215. Snitz,B.E., Macdonald-III,A.W., and Carter,C.S., 2006. Cognitive deficits in unaffected first-degree relatives of schizophrenia patients: a meta-analytic review of putative endophenotypes. Schizophrenia Bulletin 32, 179-194. Sprong,M., Becker,H.E., Schothorst,P.F., Swaab,H., Ziermans,T.B., Dingemans,P.M., Linszen,D., and Van Engeland,H., 2008. Pathways to psychosis: a comparison of the pervasive developmental disorder subtype Multple Complex Developmental Disorder and the "At Risk Mental State". Schizophrenia Research 99, 38-47. Stahlberg,O., Soderstrom,H., Rastam,M., and Gillberg,C., 2004. Bipolar disorder, schizophrenia, and other psychotic disorders in adults with childhood onset AD/HD and/or autism spectrum disorders. Journal of Neural Transmission 111, 891-902. Van Engeland,H. and Van der Gaag,R.J., 1994. MCDD in childhood: a precursor of schizophrenic spectrum disorders. Schizophrenia Research 11, 197. Wechsler, D., 1997. Wechsler Adult Intelligence Scale-III NL: Afname en scoringshandleiding [Manual]. Psychological Corporation Ltd., Harcourt Publishers. Wechsler, D., 2002. Wechsler Intelligence Scale for Children-III NL: Handleiding en verantwoording [Manual]. Psychological Corporation Ltd., Harcourt Assessment.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 89

Mirjam Sprong | Adolescents at risk of psychosis Wood,S.J., Pantelis,C., Proffitt,T., Phillips,L.J., Stuart,G.W., Buchanan,J.A., Mahony,K., Brewer,W., Smith,D.J., and McGorry,P.D., 2003. Spatial working memory ability is a marker of risk-for-psychosis. Psychological Medicine 33, 1239-1247. Zammit,S., Allebeck,P., David,A.S., Dalman,C., Hemmingsson,T., Lundberg,I., and Lewis,G., 2004. A longitudinal study of premorbid IQ score and risk of developing schizophrenia, bipolar disorder, severe depression, and other nonaffective psychoses. Archives of General Psychiatry 61, 354-360.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 90

Mirjam Sprong | Adolescents at risk of psychosis

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 91

Mirjam Sprong | Adolescents at risk of psychosis

Chapter 4

Facial affect processing in adolescents at high risk for psychosis

Mirjam Sprong a, Hanna Swaab b, Leo de Sonneville b, Tim Ziermans a, Bertine Lahuis a, Herman van Engeland a, Patricia Schothorst a Submitted for publication

a

Rudolf Magnus Institute of Neuroscience/Department of Child and Adolescent Psychiatry, University Medical Center Utrecht, the Netherlands b Department of Clinical Child and Adolescent Studies, University of Leiden, the Netherlands

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 92

Mirjam Sprong | Adolescents at risk of psychosis

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 93

Mirjam Sprong | Adolescents at risk of psychosis

Abstract The aims of this study were to test the hypothesis that facial affect processing is impaired in adolescents at high-risk for psychosis, and to investigate the building-block view of social cognition, which states that intact ‘lower-level’ nonsocial cognitive skills are necessary for ‘higher-level’ social cognition. For this purpose, facial affect recognition and ‘lower-level’ cognitive skills, i.e. attention/working memory, pattern and face recognition, were assessed in two groups of high-risk adolescents and nonpsychiatric controls (n = 81). The first high-risk group consisted of adolescents with ‘prodromal-like’ symptoms (n = 37). The second high-risk group consisted of adolescents with Multiple Complex Developmental Disorder, a subtype of Pervasive Developmental Disorder-Not Otherwise Specified (n = 29). Neither of the two high-risk groups showed overall impairments in the accuracy of recognizing facial expressions. However, the MCDD group showed specific deficits in the accuracy of recognizing fearful expressions, and an overall reduction in processing speed. Consistent with the building-block view of social cognition, attention/working memory, abstract visuospatial processing skills and face recognition skills each accounted for a unique amount of variance in facial affect processing.

1. Introduction Psychotic episodes are part of the syndromes of schizophrenia and other psychotic disorders, but they may also occur in the affective disorders (American Psychiatric Association 1994). However, the fact that there are other disorders that are associated with elevated risks of psychotic symptoms and schizophrenia spectrum disorders, including the pervasive developmental disorders (Mouridsen et al. 2007; Stahlberg et al. 2004), personality disorders (Benvenuti et al. 2005; Dowson et al. 2002; Rodriguez Solano and Gonzalez 2000), and genetic syndromes such as Klinefelter (DeLisi et al. 1994; Kunugi et al. 1999; Van Rijn et al. 2006), and 22q11-deletion syndrome (Baker and Skuse 2005; Debbane et al. 2006; Murphy et al. 1999; Vorstman et al. 2006), indicates that there are many different developmental pathways to psychosis. Comparing vulnerability markers for psychosis in populations with different pathways to psychosis is of great interest, because it may ultimately give more insight into the underlying pathology and the different manifestations of the psychotic syndrome. Neurocognitive and social impairments have frequently been identified as potential vulnerability markers for psychosis (e.g. Johnstone et al. 2005; Niemi et al. 2003; Snitz et al. 2006). Green et al. (2000) demonstrated that these impairments are interrelated in individuals with schizophrenia. However, as they and several other authors pointed out, those associations may be (partially) mediated by deficits in social cognition

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 94

Mirjam Sprong | Adolescents at risk of psychosis (Addington et al. 2006; Kee et al. 1998; Penn et al. 1997). Social cognition is defined as “the mental operations underlying social interactions, which include processes involved in perceiving, interpreting, and generating responses to the intentions, dispositions, and behaviors of others” (Green et al. 2005). One of the most widely studied social cognitive domains in schizophrenia is affect processing. There is ample evidence that individuals with schizophrenia have difficulties in recognizing and discriminating between other people’s facial expressions (reviewed by Edwards et al. 2002; Mandal et al. 1998; Mueser et al. 1997). However, some issues remain unclear, for example whether they have difficulties in processing all or specific emotions, whether the impairment is specific or explained by generalized poor performance, and whether it is trait- or state-dependent. Facial affect processing impairment is also a potential vulnerability marker for psychosis, because it has been observed in individuals with a susceptibility to psychosis, i.e. in siblings of schizophrenia patients (Kee et al. 2004), and individuals with schizotypal personality disorder or elevated levels of schizotypal traits (Combs et al. 2006; Combs and Penn 2004; Green et al. 2001 and 2003; Mikhailova et al. 1996; Poreh et al. 1994; Waldeck and Miller 2000). Positive correlations between schizotypal traits and facial affect processing impairment have also been reported (Meyer and Shean 2006; Van 't Wout et al. 2004). However, findings are inconsistent, because no impairment was found in a few other studies, i.e. in relatives of schizophrenia patients (Bolte and Poustka 2003; Toomey et al. 1999), and in individuals with elevated scores on schizotypy scales (Toomey and Schuldberg 1995). Also, Shean et al. (2007) found no significant correlations between schizotypal traits and the ability to correctly identify emotions from facial cues. Based on the observation that attention deviance in children with a genetic risk of schizophrenia predicted social functioning later in life, Cornblatt et al. (1992) proposed a model for the interaction between neurocognitive and social impairment in individuals with a biological vulnerability for schizophrenia. According to this model, chronic, earlyonset attention problems cause an inability to adequately process social information. As the individual grows older and interpersonal interactions become more complex and demanding, the social cognitive deficit becomes more debilitating, resulting in social maladjustment. This model is consistent with the building-block view of social cognition (described in: Penn et al. 1997). In this view, ‘lower-level’, nonsocial neurocognitive skills such as attentional capacity represent a necessary - but not sufficient - condition for ‘higher-level’, social cognitive skills such as the recognition of facial emotions. There is evidence from studies in schizophrenia to support these models. Firstly, facial affect processing has been associated with nonsocial neurocognitive functioning, in particular selective attention/working memory, abstraction/flexibility, and memory (Addington and Addington 1998; Brüne 2005; Bryson et al. 1997; Kee et al. 1998; Kohler et al. 2000;

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 95

Mirjam Sprong | Adolescents at risk of psychosis Pinkham and Penn 2006; Poole et al. 2000; Sachs et al. 2004; Schneider et al. 1995; Whittaker et al. 2001). Secondly, facial affect processing has been associated with social functioning (Cohen et al. 2006; Hooker and Park 2002; Ihnen et al. 1998; Mueser et al. 1996; Penn et al. 1996; Pinkham and Penn 2006; Poole et al. 2000). Thirdly, some studies have shown that facial affect processing moderates the relationship between neurocognitive and social functioning (Addington et al. 2006; Nienow et al. 2006; Pinkham and Penn 2006). The first aim of this study is to test the hypothesis that facial affect processing is impaired in adolescents at high risk for psychosis. As pointed out by De Sonneville et al. (2002), accuracy as well as a speed of processing other people’s facial emotions are important for adaptive social functioning, so both measures will be assessed. Because individuals with different developmental pathways to psychosis may display different vulnerability markers for psychosis, and thus different patterns of neurocognitive impairment, two groups of high-risk adolescents are included. The first high-risk group consists of help-seeking adolescents with an At Risk Mental State (ARMS), i.e. adolescents that are referred by mental health care professionals for having symptoms that are associated with the prodromal phase of a psychotic episode, such as a functional decline, subtle deviations in thought, emotion, and perception, and subthreshold psychotic symptoms. Follow-up studies have shown that ARMS individuals are at imminent risk of developing a psychotic episode, with transition rates ranging from 9 to 54% after 6 to 12 months (e.g. Cannon et al. 2008; Olsen and Rosenbaum 2006). When this study was set up, there were no published reports on facial affect processing in individuals with an ARMS. Based on the notion that facial affect processing impairment may be a vulnerability marker for psychosis, we hypothesized that such an impairment would be present in adolescents with an ARMS. The second high-risk group consists of adolescents with prepubertal diagnoses of Multiple Complex Developmental Disorder (MCDD), a subtype of the Pervasive Developmental Disorders - Not Otherwise Specified (PDD-NOS; Buitelaar et al. 1999a; Cohen et al. 1986; Towbin 1997). MCDD is characterized by early childhood-onset affect regulation difficulties, high levels of anxiety, odd or disturbed social relationships, and mild to severe thought disorder (Cohen et al. 1994). A follow-up study of 55 children with MCDD revealed a considerably elevated risk of schizophrenia spectrum disorders; 22% that had been followed until adolescence, and 64% that had been followed until young adulthood had developed schizophrenia-spectrum disorders (Van Engeland and Van der Gaag 1994). Also, in an earlier paper we reported that 78.1% of individuals diagnosed with MCDD in childhood met research criteria for ARMS when they were interviewed in adolescence (Sprong et al. 2008). Affect processing impairments have frequently been reported for individuals with PDD, mainly autism and Asperger’s disorder (e.g. Adolphs et al. 2001; Braverman et al. 1989;

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 96

Mirjam Sprong | Adolescents at risk of psychosis Celani et al. 1999; Gross 2005; Hobson et al. 1988; Pelphrey et al. 2002). However, the extent and specificity of the deficit are unclear and subject of considerable scrutiny. Few studies have compared the facial affect recognition abilities in individuals with PDD-NOS with those in nonpsychiatric controls. In a study by Buitelaar et al. (1999b), but not in a study by Serra et al. (1998), PDD-NOS children showed facial affect recognition impairment compared to nonpsychiatric controls. To our knowledge, there is only one study on facial affect recognition in MCDD (Herba et al. 2007). In that study, no differences were found between children meeting the MCDD criteria (of which some did not meet research criteria for PDD-NOS), and children with PDD-NOS who did not meet the MCDD criteria. Unfortunately, no comparison was made with nonpsychiatric controls. In sum, the available evidence regarding facial affect processing in MCDD is inconclusive. However, because individuals with MCDD are considered to be at high risk for psychosis, and because MCDD is part of the autism spectrum, we hypothesized that facial affect processing impairments will be present in this group. We had no specific hypotheses regarding the comparison of the two high-risk groups. The second aim of this study is to investigate the building-block view of social cognition. The brain regions that are involved in facial affect processing are part of a complex neural system, referred to as the social cognition network, in which specific loci are involved in processing specific social information (e.g. Burns 2004; Grady and Keightley 2002). For example the amygdala appears to be involved in processing facial affect, and a region in the ventral-occipital cortex, i.e. ‘the fusiform face area‘, in processing facial identity. According to Grady & Keightley (2002), the different modules in the social cognition network are likely to be interconnected to support adaptive behavior in complex social situations. Therefore we hypothesize that information processing skills that are involved in the recognition of facial identity are also involved in the recognition of facial affect. In fact, tasks assessing facial identity processing have frequently been used as control tasks to investigate the specificity of facial emotion processing impairment in schizophrenia, although this has been criticized because tasks have not adequately been matched on design and difficulty (Edwards et al. 2002). It has been suggested that facial affect processing is associated with nonface visuospatial processing, i.e. the processing of patterns or objects (Asthana et al. 1998; De Sonneville et al. 2002). Two studies found an association between facial emotion processing and visual processing of letters in individuals with schizophrenia (Addington and Addington 1998; Kee et al. 1998). In a third study, the facial affect naming impairment of individuals with schizophrenia was no longer significant after including object naming in the analysis (Whittaker et al. 2001). So in addition to attention, which is suggested by Cornblatt et al.’s (1992) model, we will also examine abstract visuospatial (pattern) and facial identity processing abilities. Based on the building-block view we hypothesize that each of these ‘lower-level’ neurocognitive skills will contribute unique variance to facial emotion processing performance.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 97

Mirjam Sprong | Adolescents at risk of psychosis

2. Method 2.1. Participants The first high-risk group consisted of help-seeking adolescents meeting the research criteria for ARMS as defined within the European Prediction of Psychosis Study (Klosterkötter et al. 2005) and the Dutch Prediction of Psychosis Study (Sprong et al. 2008), i.e. having one or more of the following: (1) attenuated positive symptoms, (2) brief, limited, or intermittent psychotic symptoms, (3) a significant reduction in level of functioning combined with a genetic risk of psychosis, or (4) two or more of a selection of nine ‘basic symptoms’, i.e. subtle deficits in cognitive, perceptual, and motor functioning. The first three criteria were assessed with the Structured Interview for Prodromal Syndromes (SIPS; McGlashan et al. 2001; Miller et al. 1999) which also includes a Global Assessment of Functioning (GAF) scale. The fourth criterion was assessed with the Bonn Scale for the Assessment of Basic Symptoms-Prediction List (BSABS-P; Schultze-Lutter and Klosterkötter 2002). The second high-risk group consisted of adolescents with prepubertal clinical diagnoses of PDD-NOS (American Psychiatric Association 1994), who additionally met Cohen et al.’s (1994) diagnostic criteria for MCDD (Table 1). Diagnoses were confirmed by expert clinical opinion after psychiatric examination including the Autism Diagnostic InterviewRevised (Lord et al. 1994), and an additional parent-interview in which the presence of MCDD symptoms was thoroughly examined. Subsequently, the MCDD criteria were rated using the information present in the medical records. Nonpsychiatric Control (NPC) adolescents were recruited by distributing information brochures about the research project at several secondary schools in the region of Utrecht. They were excluded if they or a first degree relative had a history of any psychiatric illness, or if they had a second degree relative with a history of a psychotic disorder. NPC adolescents were also screened using the SIPS and the BSABS-P interviews, and were excluded if they met any of the ARMS criteria. All included participants were aged between 12 and 18 years, and had a verbal IQ ≥ 75, as assessed with Wechsler’s Intelligence Scales (1997 and 2002). They all signed an informed consent, and for those younger than 16, the primary caretaker(s) co-signed. Participants were screened for physical illness by filling out a health checklist, and those with possible endocrinological or cerebral disorders were excluded from the study. The use of psychotropic medication was an exclusion criterion for the NPC adolescents, but not for the high-risk adolescents. At the time of inclusion, none of the participants had ever experienced a psychotic episode, defined as the presence of seriously disorganizing positive symptoms, i.e. a score of 6 on any of the items of the SIPS Positive symptoms subscale, or on the SIPS item “Odd behavior or appearance”, with a duration of more than one week.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 98

Mirjam Sprong | Adolescents at risk of psychosis

2.2. Materials 2.2.1. Attention/working memory To measure attention/working memory, the computer-administered Continuous Performance Test-Identical Pairs version 2.0 was selected (CPT-IP; Cornblatt 2000). Participants were asked to respond as quickly as possible by releasing a mouse key held in the dominant hand whenever two identical visual stimuli were presented in a row (fixed stimulus interval 950 ms, fixed stimulus duration 50 ms; no distraction condition).

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 99

Mirjam Sprong | Adolescents at risk of psychosis This task has been described as demanding of both attention and working memory capacity, because each stimulus must first be processed, and then held in memory until it can be compared with the next stimulus to determine whether there is an exact match (Cornblatt 2000). In the first part stimuli were 4-digit numbers, and in the second part stimuli were nonsense shapes, which are considered to be verbal and nonverbal stimuli respectively. Both parts consisted of 150 trials. Dependent variables were accuracy (% hits) and speed (mean reaction time (RT) hits) for the two parts separately.

2.2.2. Pattern recognition The ability to recognize abstract visuospatial patterns was assessed with the Feature Identification (FI) subtask of the computer-administered Amsterdam Neuropsychological Tasks Program (ANT; De Sonneville 2003). Participants were asked to determine whether a predefined target pattern, i.e. a 3 x 3 matrix consisting of a combination of 6 white and 3 red blocks, was present in a succession of sets of four 3 x 3 matrices consisting of various combinations of red and white blocks (Figure 1). They were asked to respond as quickly and accurately as possible by pressing either YES (target present) or NO (target not present). As in all of the ANT tasks used in this study, YES and NO answers were assigned to the right and left mouse keys respectively for right-handed subjects, and vice versa for left-handed subjects. The target pattern was presented only at the beginning of the task, and had to be kept in mind during the whole task. Each stimulus (consisting of a set of four 3 x 3 matrices) was preceded by a warning signal (‘+’) of 500 ms, and remained on the screen until the participant pressed a response key. Thus, the presentation time was variable and equal to the RT (200-8000 ms). The post-response interval (PRI) was 1200 ms. There were 40 trials which required a YES response, and 40 trials which required a NO response, presented in random order. In 50% of the YES trials, the target pattern was similar to the three non-target patterns, which made target detection difficult. In the other half of the YES trials the target pattern was dissimilar to the three non-target patterns, which made target detection easy. Likewise, in 50% of the NO trials, all patterns looked similar to the target, whereas in the other half of the NO trials, all patterns looked dissimilar to the target. Dependent measures were accuracy (% errors, i.e. false alarms and misses) and speed (mean RT of the correct responses, i.e. hits and correct rejections) for the Similar and Dissimilar conditions separately.

2.2.3. Face recognition The ability to process abstract facial information was assessed with the Facial Recognition (FR) subtask of the ANT (De Sonneville 2003). Participants had to determine whether a target face was present in a set of four faces. They were asked to respond as quickly and accurately as possible by pressing either YES (target is present) or NO (target

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 100

Mirjam Sprong | Adolescents at risk of psychosis is not present). For this task, digital, high-quality color photos of faces with a neutral expression were used. There were photos of 20 different models (5 boys, 5 girls, 5 men, 5 women), all dressed in the same black t-shirt. In this task, the target (i.e. the to be remembered face) varied with each trial. It was presented for 2500 ms and then disappeared from the screen. After 500 ms, the stimulus (i.e. a set of four faces) was presented, which remained on the screen until the participant pressed a response key. Presentation time of the stimulus was thus variable and equal to the RT (300-8000 ms). The PRI was 1000 ms. There were 40 trials, half of which required a YES response, and half of which required a NO response, presented in random order. The gender (male/female) and age category (adult/child) of the target always matched the gender and age category of the four faces in the stimulus set. Measures of accuracy (% errors) and speed (mean RT of the correct responses) were obtained. Figure 1. Signal types used in the Feature Identification task. The YES key should be pressed when target is present and the NO key when the target is not present.

2.2.4. Facial affect recognition The ability to recognize facial emotions was assessed with the Identification of Facial Emotions (IFE) subtask of the ANT (De Sonneville 2003). Participants were asked to determine whether a target emotion was expressed by a succession of faces that could express any of the following eight emotions: Happy, Sad, Angry, Fearful, Disgust, Surprise, Shame, Contempt. They were asked to respond as quickly and accurately as possible by pressing either YES (target emotion is expressed) or NO (target emotion is not expressed). The total stimulus set consisted of 32 digital, high-quality, color photos of four adult models (two men, two women), each showing the eight emotions. The

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 101

Mirjam Sprong | Adolescents at risk of psychosis complete task has eight different parts, i.e. one for each emotion, but only the first four parts were used in this study (i.e. Happy, Sad, Angry, and Fearful). In each part, participants were instructed to focus on a particular emotion. Each part consisted of 40 trials, half of which were faces that expressed the target emotion, and half of which are faces that expressed a random selection of the other seven emotions. Each stimulus was preceded by a warning signal (‘+’) of 500 ms, and remained on the screen until the participant pressed a response key. Presentation time was thus variable and equal to the RT (250-8000 ms). The PRI was 1000 ms. Dependent measures were accuracy (% errors) and speed (mean RT of the correct responses) for each of the four emotions, as well as averaged over the four conditions.

2.3. Statistical analyses Assumptions underlying the use of parametric tests were examined for each dependent variable using the Kolmogorov-Smirnov test and the Levene’s test, supplemented by visual inspections of the data distributions and residual plots. All analyses were 2-tailed, with α set at .05. Demographics were analyzed by ANOVA and nonparametric tests. Participants were excluded from the task analysis when their performance accuracy was extremely poor (i.e. CPT-IP hit rate < 20%; FI, FR, or IFE error rate > 40%), or in case of extreme RT values (> 3 times the inter-quartile range). A series of univariate (repeated measures) ANCOVAs controlling for age and gender was performed on the various outcome measures of the CPT-IP, FI, FR, and IFE tasks, with planned comparisons of the high-risk samples with the NPC sample. F-statistics and pvalues are presented, as well as effect size estimates Pearson’s r. Effect sizes .10 ≤ r < .30 were considered a small effect, .30 ≤ r < .50 a medium effect, and r ≥ .50 a large effect. To visualize the performance profiles of the high-risk groups relative to the NPC group, mean z-values adjusted for age and gender ± SE were calculated. Where appropriate, z-values were reversed so that negative z-values always represented a poorer performance in comparison with the NPCs. To examine whether the different ‘lower-level’, nonsocial neurocognitive skills each account for a significant amount of the variance in facial affect processing, two hierarchical regression analyses were conducted, one for facial affect processing accuracy, and one for speed of facial affect processing. In both regression analyses, the average IFE performance over the four emotions was used as dependent variable. Age and gender were entered together in the first step, group membership (transformed into two dummy variables: ARMS vs. NPC and MCDD vs. NPC) was entered in the second step, attention/working memory (average of CPT-IP Symbols and Figures) in the third, pattern recognition (FI Similar) in the fourth, and facial recognition (FR) in the last step. For each step, raw and standardized beta-coefficients (B and β) and significance values are presented, as well as the change statistics and corresponding significance values.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 102

Mirjam Sprong | Adolescents at risk of psychosis

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 103

Mirjam Sprong | Adolescents at risk of psychosis

3. Results 3.1. Sample characteristics Pattern, face and affect processing data were available for 37 ARMS, 29 MCDD and 81 NPC adolescents. There were missing data for three participants on the CPT-IP Figures task and for two participants on the CPT-IP Symbols task due to technical problems. The total numbers of excluded participants per task were: CPT-IP: 3, FI: 3, FR: 1, and IFE: 7. Demographic and sample characteristics are displayed in Table 2. Of the ARMS sample, 40.5% met one, 48.6% met two, and 10.8% met three of the criteria for putatively prodromal state. Figure 2. Accuracy and speed of information processing in adolescents at high risk for psychosis relative to nonpsychiatric controls (mean z-values adjusted for age and gender ± SE)

Note. MCDD = Multiple Complex Developmental Disorder; ARMS = At Risk Mental State; CPT = Continuous Performance Test; FI = Feature Identification; FR = Facial Recognition; IFE = Identification of Facial Emotions

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 104

Mirjam Sprong | Adolescents at risk of psychosis The MCDD sample met a mean number of 8.79 (SD = 2.19) MCDD criteria, and 23/29 (79.3%) also met at least one of the ARMS criteria. Statistical comparisons revealed age, gender and VIQ differences between the three groups. The two high-risk groups did not differ in GAF-scores. The majority of the high-risk patients were using a psychopharmaceutical, with antipsychotic medication being the most prevalent in the MCDD group, and antidepressant medication in the ARMS group.

3.2. Hypotheses testing The information processing performance profiles of the high-risk groups relative to the NPC group are visualized in Figure 2.

3.2.1. Attention/working memory Repeated measures ANCOVAs with stimulus type (Figures vs. Symbols) as withinsubjects variable, demonstrated that the groups did not differ in processing accuracy (F(2,136) = 2.269, p = .107; rMCDDvs.NPC = .14 and rARMSvs.NPC = .14). However, the effect sizes suggest that there may be small group effects that did not reach significance due to a lack of power (calculated as β = .455). There was no main effect of stimulus type (F(1,136) = 0.146, p = .703; rFiguresvs.Symbols = .03), and no stimulus type x group interaction effect (F(2,136) = 0.077, p = .925). For processing speed there were also no main effects of group (F(2,136) = 0.324, p = .724; rMCDDvs.NPC = .09 and rARMSvs.NPC = .04), and stimulus type (F(1,136) = 0.096, p = .758; rFiguresvs.Symbols = .03), nor a stimulus type x group interaction effect (F(2,136) = 0.151, p = .860).

3.2.2. Pattern recognition Repeated measures ANCOVAs with task condition (Dissimilar vs. Similar) as withinsubjects variable, revealed that for accuracy there was no main effect of group (F(2,139) = 1.244, p = .291; rMCDDvs.NPC = .07 and rARMSvs.NPC = .10), no main effect of task condition (F(1,139) = 0.579, p = .448; rDissimilarvs.Similar = .06), and no group x task condition interaction effect (F(2,139) = 1.243, p = .292). For processing speed, there was a main effect of group (F(2,139) = 6.253, p = .003; rMCDDvs.NPC = .33 and rARMSvs.NPC = .09). The MCDD group generally needed more time to recognize patterns than the NPC group (p = .001; Dissimilar rMCDDvs.NPC = .31 and Similar rMCDDvs.NPC = .27). There were no differences between the ARMS group and the NPC group (p = .391; Dissimilar rARMSvs.NPC = .08 and Similar rARMSvs.NPC = .06). There was also a main effect of task condition (F(1,139) = 25.928, p < .001; rDissimilarvs.Similar = .40), indicating that similar patterns were processed slower than dissimilar patterns. The group x task condition interaction effect approached statistical significance (F(2,139) = 2.860, p = .061). Post hoc analyses showed a stronger increase in RT with increasing

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 105

Mirjam Sprong | Adolescents at risk of psychosis task difficulty in the MCDD group compared to the NPC group (F(1,104) = 5.923, Bonferroni corrected p = .034).

3.2.3. Face recognition ANCOVAs demonstrated that the group differences in accuracy of facial recognition approached statistical significance (F(2,141) = 2.721, p = .069). The MCDD group made more errors than the NPC group (p = .023; rMCDDvs.NPC = .21), but there was no difference between the ARMS group and the NPC group (p = .405; rARMSvs.NPC = .10). There were group differences in processing speed (F(2,141) = 9.194, p < .001). The MCDD group generally needed more time to recognize faces than the NPC group (p < .001, rMCDDvs.NPC = .33), whereas the difference between the ARMS group and the NPC group failed to reach statistical significance (p = .090, rARMSvs.NPC = .14).

3.2.4. Facial affect recognition ANCOVAs showed that the groups did not differ in accuracy of facial affect recognition (F(2,135) = 0.949, p =.390; rMCDDvs.NPC = .11 and rARMSvs.NPC = .06). There were however, group differences in processing speed (F(2,135) = 3.740, p = .026). The MCDD group needed more time to recognize facial emotions than the NPC group (p = .007, rMCDDvs.NPC = .23), but there was no difference between the ARMS group and the NPC group (p = .540, rARMSvs.NPC = .05). When the four basic emotions were analyzed separately, group differences were revealed for the accuracy of recognizing Fear (F(2,135) = 4.727, p = .010). The MCDD group made more errors than the NPC group (p = .004, rMCDDvs.NPC = .25), but there was no difference between the ARMS group and the NPC group (Fear p = .818, rARMSvs.NPC = .02). There were also group differences in processing speed for the emotions Happy (F(2,135) = 5.444, p = .004), and Fear (F(2,135) = 3.674, p = .028), while the group differences for Sad approached statistical significance (F(2,135) = 2.811, p = .064). The MCDD group needed longer than the NPC group to recognize Happy (p = .001, rMCDDvs.NPC = .28), Fear (p = .010, rMCDDvs.NPC = .22) and Sad (p = .021, rMCDDvs.NPC = .20), whereas the ARMS group did not differ from the NPC group on these emotions (Happy p = .139, rARMSvs.NPC = .13; Fear p = .894, rARMSvs.NPC = .01; Sad p = .368, rARMSvs.NPC = .08).

3.2.5. Pattern recognition compared with face recognition Repeated measures ANCOVAs with task type (FI Dissimilar vs. FR) as within-subjects variable, showed that for processing accuracy (Figure 3a) there was no main effect of group (F(2,138) = 0.799, p = .452), and no main effect of task type (F(1,138) = 0.941, p = .334). However, there was a significant group x task interaction effect (F(2,138) = 4.216, p = .017). Post hoc analyses revealed a significantly larger decrease in accuracy from simple pattern recognition to facial recognition in the MCDD group compared to

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 106

Mirjam Sprong | Adolescents at risk of psychosis the NPC group (F(1,103) = 7.567, Bonferroni corrected p = .014), whereas no difference was observed between the ARMS group and the NPC group (F(1,112) = 0.970, Bonferroni corrected p = .654). For processing speed (Figure 3b), there was a main effect of group (F(2,138) = 9.930, p < .001), with the MCDD group generally being slower than the NPC group (p < .001; FI Dissimilar rMCDDvs.NPC = .31 and FR rMCDDvs.NPC = .33). The ARMS group did not differ from the NPC group (p = .104; FI Dissimilar rARMSvs.NPC = .08 and FR rARMSvs.NPC = .14). There was also a main effect of task type (F(1,138) = 15.099, p < .001), indicating that simple pattern recognition was generally faster than face recognition. There was also a significant group x task type interaction effect (F(2,138) = 4.525, p = .012). Post hoc analyses revealed a significantly larger increase in RT from simple pattern recognition to facial recognition in the MCDD group than in the NPC group (F(1,103) = 6.437, Bonferroni corrected p = .026). In sum, all participants needed more time to recognize faces than familiar patterns amongst dissimilar patterns. However, for MCDD adolescents the increase in task difficulty led to both a larger increase in errors and longer RTs. Repeated ANCOVAs with task type (FI Similar vs. FR) as within-subjects variable, showed that for processing accuracy (Figure 3c) there was no main effect of group (F(2,138) = 1.762, p = .176), and no main effect of task type (F(1,138) = 0.035, p = .851). The group x task interaction effect failed to reach statistical significance (F(2,138) = 2.429, p = .092). For processing speed (Figure 3d), there was a main effect of group (F(2,138) = 8.036, p < .001), with the MCDD group having longer RTs than the NPC group (p < .001; FI Similar rMCDDvs.NPC = .27 and FR rMCDDvs.NPC = .33). The ARMS group did not differ from the NPC group (p = .188; FI Similar rARMSvs.NPC = .06 and FR rARMSvs.NPC = .14). There was no main effect of task type (F(1,138) = 0.955, p = .330), nor a significant group x task type interaction effect (F(2,138) = 0.548, p = .579).

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 107

Mirjam Sprong | Adolescents at risk of psychosis Figure 3. Accuracy (A, B) and processing speed (C, D) of pattern recognition (FI) vs. face recognition (FR) in two groups of adolescents at high risk for psychosis and nonpsychiatric controls (estimated marginal means adjusted for age and gender ± SE)

Note. ARMS = At Risk Mental State; NPC = Nonpsychiatric Control; MCDD = Multiple Complex Developmental Disorder; FI dis = Feature Identification Dissimilar; FI sim = Feature identification Similar; FR = Facial Recognition

3.2.6. Face recognition compared with facial affect recognition Repeated measures ANCOVAs with task type (FR vs. IFE) as within-subjects variable, revealed that for performance accuracy (Figure 4a) there was no main effect of group (F(2,134) = 1.584, p = .209), no main effect of task type (F(1,134) = 0.836, p = .362), and no group x task interaction effect (F(2,134) = 0.823, p = .441). For processing speed (Figure 4b), there was a main effect of group (F(2,134) = 6.842, p = .001), with longer RTs in the MCDD group compared to the NPC group (p < .001; FR rMCDDvs.NPC = .33 and IFE-all rMCDDvs.NPC = .23). The ARMS group did not differ from the NPC group (p = .236; FR rARMSvs.NPC = .14 and IFE-all rARMSvs.NPC = .05). There was also a main effect of task type (F(1,134) = 28.663, p < .001), indicating that participants generally needed more time to recognize facial identity than facial affect. There was also a group x task interaction effect (F(2,134) = 7.203, p = .001). Post hoc analyses indicated that with increasing task difficulty, the MCDD adolescents needed relatively more time

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 108

Mirjam Sprong | Adolescents at risk of psychosis to recognize facial identity than facial emotions compared to NPC adolescents (F(1,99) = 12.503, Bonferroni corrected p = .002). Figure 4. Accuracy (A) and processing speed (B) of face recognition (FR) vs. facial affect (IFE) recognition in two groups of adolescents at high risk for psychosis and nonpsychiatric controls (estimated marginal means adjusted for age and gender ± SE)

Note. ARMS = At Risk Mental State; NPC = Nonpsychiatric Control; MCDD = Multiple Complex Developmental Disorder; FR = Facial Recognition; IFE = Identification of Facial Emotions

3.2.7. Interrelationship between ‘lower-level’ neurocognitive skills and facial affect recognition Table 3 shows that the demographic variables gender, age and group membership together did not significantly predict accuracy of facial affect recognition (adjusted R2 = 0.01; F(2,129) = 0.99, p = .374), but they did significantly predict processing speed (adjusted R2 = 0.10; F(2,129) = 4.01, p = .020). Regarding group membership, it was the difference between the MCDD group and the NPC group that accounted for this effect. At each next step in the hierarchical regression analyses, the addition of ‘lower level’ information processing skills as predictor variables significantly improved the prediction of both accuracy and speed of facial affect recognition. All three ‘lower-level’ cognitive skills were significant predictors in the final regression model which predicted 22% of the variance in accuracy facial affect recognition. In contrast, with the addition of the pattern recognition and facial recognition variables, attention/working memory no longer remained a significant predictor of speed of facial affect recognition. Speed of pattern recognition and speed of facial recognition accounted for 54% of the total 70% of the total amount of variance in speed of facial affect recognition explained by the model.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 109

Mirjam Sprong | Adolescents at risk of psychosis

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 110

Continued

Mirjam Sprong | Adolescents at risk of psychosis

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 111

Continued

Mirjam Sprong | Adolescents at risk of psychosis

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 112

Mirjam Sprong | Adolescents at risk of psychosis

4. Discussion The aims of this study were to test the hypothesis that facial affect processing is impaired in adolescents at high-risk for psychosis, and to investigate the building-block view of social cognition. For this purpose, facial affect processing skills and ‘lower-level’ neurocognitive skills hypothesized to be necessary for facial affect processing were assessed in two groups of high-risk adolescents. The first high-risk group consisted of adolescents with ‘prodromal-like’ symptoms who met research criteria for ARMS. The second high-risk group consisted of adolescents with prepubertal diagnoses of the MCDD subtype of PDD-NOS. The results showed that neither of the two high-risk groups had impairments in the accuracy of facial affect recognition, and that attention/working memory, abstract visuospatial processing skills and face recognition skills each accounted for a unique amount of variance in facial affect processing. Since the start of this study, three papers on facial affect processing in ARMS individuals have been published. Pinkham et al. (2007) did not find impairments in either facial affect identification or discrimination in ARMS individuals. Seiferth et al. (2007) reported abnormal neural response patterns (fMRI) to both emotional and neutral faces in ARMS individuals, but the ARMS individuals did not make more errors on a facial affect discrimination task. In the study by Addington et al. (2008), ARMS individuals showed impaired facial affect identification, but facial affect discrimination was not impaired. Furthermore, the evidence for generalized facial affect processing impairment in PDDNOS and MCDD is limited and inconclusive. Thus, the results of this study as well as the literature do not provide compelling evidence for facial affect processing impairment in these two high-risk groups. A possible explanation is that facial affect processing difficulties emerge not until closer to or after the onset of frank psychosis. An alternative explanation could be that facial affect processing impairment is already present in adolescents who will go on to develop a psychotic episode, but that the rates of falsepositives in our high-risk samples were too high to discriminate between the high risk groups and the NPC group. Although the MCDD group did not show generalized deficits in the accuracy of recognizing facial expressions, specific deficits in the accuracy of recognizing fear became apparent. Specific difficulties in fear processing have frequently been reported in individuals with autism and Asperger’s disorder (Howard et al. 2000; Humphreys et al. 2007; Pelphrey et al. 2002; Rieffe et al. 2007). Based on the fact that the diagnostic criteria for MCDD include intense fears and anxieties, Herba et al. (2007) predicted differences in the processing of threatening expressions (i.e. fear and anger) between children meeting the MCDD criteria (of whom some did not meet the research criteria for PDD-NOS), and children with PDD-NOS who did not meet the MCDD criteria. However, no such differences were found. So the evidence suggests that specific

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 113

Mirjam Sprong | Adolescents at risk of psychosis impairments in the recognition of fear may be associated with the autism spectrum, rather than only with the PDD-NOS subtype MCDD. The MCDD adolescents also showed a reduced speed of affect recognition, as evidenced by longer reaction times on the task. However, this reduced processing speed was also observed for the recognition of abstract visual patterns and facial identity. Moreover, there was evidence of a stronger decrease in speed of processing with increasing task difficulty in adolescents with MCDD compared to NPC adolescents. The fact that the MCDD group did not show longer RTs on the CPT-IP task may be explained by the fact that unlike the other tasks that were self-paced, the CPT-IP had fixed stimulus durations and stimulus blank times, which may have led to ceiling effects regarding RTs. Processing speed abnormalities have frequently been reported for individuals with PDD(NOS). Using the ANT-tasks, Serra et al. (2003) found reduced processing speeds for the recognition of abstract visuospatial patterns and facial identity in children with PDD-NOS (the IFE subtask was not assessed). In a different task paradigm, Swaab-Barneveld et al. (2000) found longer reaction times on a self-paced sustained attention task in children with PDD compared to nonpsychiatric controls. Also in a different task paradigm, children with PDD-NOS were found to need more time to carry out the same number of serial letter comparisons in working memory, and this time increased stronger with increasing task load in the PDD-NOS sample than in typically developing controls (Althaus et al. 1996). Lastly, individuals with autism showed intact processing speeds in tasks with low cognitive demand, but impaired processing speed in a task with high cognitive demands (Luna et al. 2007). So the evidence suggests that individuals with PDD-NOS have a generalized impairment of speed of processing complex stimulus configurations. In a recent paper, Rodriguez-Sanchez et al. (2007) argued that reduced processing speed as assessed with the Digit Symbol (DS) Substitution subtest of the Wechsler Intelligence Scales (1997) may be a “core cognitive deficit in schizophrenia”, i.e. a process underlying a broad diversity of cognitive disturbances. In fact, poor DS performance has repeatedly been reported for ARMS individuals (Brewer et al. 2005; Hawkins et al. 2004; Keefe et al. 2006; Pukrop et al. 2007). However, in the present study processing speed was not impaired in the ARMS group, which may be explained by differences in the operationalization of processing speed. For example, abilities that are necessary for both a good DS performance and a short RT on the ANT recognition tasks probably include psychomotor speed, short-term visual memory, and attention. However, good DS performance also implies associative learning (Groth-Marnat 1999), whereas this is not relevant for RT on the ANT recognition tasks. The observation that each of the lower-level neurocognitive skills, i.e. attention/working memory, abstract visuospatial processing and face recognition skills accounted for a unique amount of variance in facial affect processing provides support for the building-

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 114

Mirjam Sprong | Adolescents at risk of psychosis block view of social cognition. This finding suggests that facial affect recognition is perhaps better characterized by a range of neurocognitive skills rather than by one specific skill. However, a fair amount of variance in facial affect processing performance remained unexplained, so it is likely that other factors, including other ‘lower-level’ neurocognitive skills that were not entered in this model, may contribute to facial affect processing. This does not rule out the possibility that there is also a unique ‘facial affect processing skill’. To the best of our knowledge, this is the first study in which the building block view has been tested, so replication and extension of the findings is needed. A limitation of this study is that the use of psychotropic medication was not an exclusion criterion for the high-risk groups, and that the effects of the different types of medication on neurocognitive performance are still poorly understood. Medication use was not entered as a factor in the ANCOVAs because it led to a dramatic reduction in statistical power. Secondly, the groups were not matched on sample size. This may be problematic in case the variances of the outcome variables are not equal across groups. However, there were only two variables for which this was the case, i.e. % errors FR and RT IFE-Happy (the variance ratios were 3.8 and 3.0 respectively). The results of the statistical analyses of these two variables should be interpreted with some caution. Thirdly, we unexpectedly did not find significant attention/working memory impairments in either of the high-risk groups. In many of the ARMS studies significant CPT-IP impairments have been observed (Francey et al. 2005; Hambrecht et al. 2002; Hawkins et al. 2004; Lencz et al. 2006; Pukrop et al. 2006), although negative findings have also been reported (Keefe et al. 2006; Pukrop et al. 2007). In an unpublished paper (Sprong et al.), we report on significant attention/working memory impairments as measured with the CPT-IP in both the ARMS group (r = .15) and the MCDD group (r = .19). The effect sizes were slightly larger but comparable to those in the present study (ARMS-NPC r = .14 and MCDD-NPC r = .14). It is likely that the group differences in the present study did not reach statistical significance, because the sample sizes are smaller than in our earlier paper. As mentioned in the introduction, facial affect processing impairment has been associated with schizotypal traits and with a genetic risk for psychosis. In an earlier paper on larger ARMS and MCDD samples of the DUPS study, we reported that both high-risk groups had significantly higher scores on a self-report schizotypy scale than the NPC group (Sprong et al. 2008). The effect sizes indicated that the schizotypy scores of the high-risk adolescents were on average 1 to 1.5 standard deviations above the overall mean. Furthermore, the high-risk groups also had elevated rates of individuals with at least one first or second degree relative with a history of psychotic illness, i.e. 14.3% in the ARMS sample and 13.8% in the MCDD sample (Table 2). One might speculate that if only those ARMS and MCDD adolescents with elevated schizotypy scores, or only

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 115

Mirjam Sprong | Adolescents at risk of psychosis those with a genetic risk for psychosis would be compared to NPC adolescents, facial affect recognition impairment might be detected in those high-risk subjects. Follow-up of the two high-risk groups into adulthood is necessary to establish who will make a transition to psychosis, and thus can be considered truly ‘at risk’. This will allow for testing the hypothesis that facial affect processing impairment is already present before the onset of a first psychotic episode. In addition, the predictive validity of facial affect processing impairment for the transition to psychosis could then be analyzed. Future studies in adolescents with MCDD should focus on the possible consequences of processing speed impairment on social functioning and the development of psychotic symptoms. Those studies should also include other measures of processing speed such as the DS task, which has been associated with psychosis susceptibility. Lastly, comparative research in high-risk populations with other developmental pathways to psychosis such as Klinefelter and 22q11-deletion syndrome is needed to further increase insight into the underlying pathology of psychosis.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 116

Mirjam Sprong | Adolescents at risk of psychosis

References Addington,J. and Addington,D., 1998. Facial affect recognition and information processing in schizophrenia and bipolar disorder. Schizophrenia Research 32, 171-181. Addington,J., Penn,D., Woods,S.W., Addington,D., and Perkins,D.O., 2008. Facial affect recognition in individuals at clinical high risk for psychosis. The British Journal of Psychiatry 192, 67-68. Addington,J., Saeedi,H., and Addington,D., 2006. Facial affect recognition: a mediator between cognitive and social functioning in psychosis? Schizophrenia Research 85, 142-150. Adolphs,R., Sears,L., and Piven,J., 2001. Abnormal processing of social information from faces in autism. Journal of Cognitive Neuroscience 13, 232-240. Althaus,M., De Sonneville,L.M.J., Minderaa,R.B., Hensen,L.G.N., and Til,R.B., 1996. Information processing and aspects of visual attention in children with the DSM-III-R diagnosis "Pervasive Developmental Disorder Not Otherwise Specified" (PDD-NOS): I. Focused and divided attention. Child Neuropsychology 2, 17-29. American Psychiatric Association, 1994. Diagnostic and statistical manual of mental disorders (4th edition). Washington DC: Author. Asthana,H.S., Mandal,M.K., Khurana,H., and Haque-Nizamie,S., 1998. Visuospatial and affect recognition deficit in depression. Journal of Affective Disorders 48, 57-62. Baker,K.D. and Skuse,D.H., 2005. Adolescents and young adults with 22q11 deletion syndrome: psychopathology in an at-risk group. The British Journal of Psychiatry 186, 115-120. Benvenuti,A., Rucci,P., Ravani,L., Gonnelli,C., Frank,E., Balestrieri,M., Sbrana,A., Dell'Osso,L., and Cassano,G.B., 2005. Psychotic features in borderline patients: is there a connection to mood dysregulation? Bipolar Disorders 7, 338-343. Bolte,S. and Poustka,F., 2003. The recognition of facial affect in autistic and schizophrenic subjects and their first-degree relatives. Psychological Medicine 33, 907-915. Braverman,M., Fein,D., Lucci,D., and Waterhouse,L., 1989. Affect comprehension in children with pervasive developmental disorders. Journal of Autism and Developmental Disorders 19, 301-316. Brewer,W.J., Francey,S.M., Wood,S.J., Jackson,H.J., Pantelis,C., Phillips,L.J., Yung,A.R., Anderson,V.A., and McGorry,P.D., 2005. Memory impairments identified in people at ultra-high risk for psychosis who later develop first-episode psychosis. The American Journal of Psychiatry 162, 71-78.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 117

Mirjam Sprong | Adolescents at risk of psychosis Brüne,M., 2005. Emotion recognition, 'theory of mind,' and social behavior in schizophrenia. Psychiatry Research 133, 135-147. Bryson,G., Bell,M., and Lysaker,P., 1997. Affect recognition in schizophrenia: a function of global impairment or a specific cognitive deficit. Psychiatry Research 71, 105-113. Buitelaar,J.K., Van der Gaag R., Klin,A., and Volkmar,F., 1999a. Exploring the boundaries of pervasive developmental disorder not otherwise specified: analyses of data from the DSM-IV Autistic Disorder Field Trial. Journal of Autism and Developmental Disorders 29, 33-43. Buitelaar,J.K., Van der Wees,M., Swaab-Barneveld,H., and Van der Gaag,R.J., 1999b. Theory of mind and emotion-recognition functioning in autistic spectrum disorders and in psychiatric control and normal children. Development and Psychopathology 11, 39-58. Burns,J.K., 2004. An evolutionary theory of schizophrenia: cortical connectivity, metarepresentation, and the social brain. The Behavioral and Brain Sciences 27, 831-855. Cannon,T.D., Cadenhead,K., Cornblatt,B., Woods,S.W., Addington,J., Walker,E., Seidman,L.J., Perkins,D., Tsuang,M., McGlashan,T., and Heinssen,R., 2008. Prediction of psychosis in youth at high clinical risk: a multisite longitudinal study in North America. Archives of General Psychiatry 65, 28-37. Celani,G., Battacchi,M.W., and Arcidiacono,L., 1999. The understanding of the emotional meaning of facial expressions in people with autism. Journal of Autism and Developmental Disorders 29, 57-66. Cohen,A.S., Forbes,C.B., Mann,M.C., and Blanchard,J.J., 2006. Specific cognitive deficits and differential domains of social functioning impairment in schizophrenia. Schizophrenia Research 81, 227-238. Cohen,D.J., Paul,R., and Volkmar,F.R., 1986. Issues in the classification of pervasive and other developmental disorders: toward DSM-IV. Journal of the American Academy of Child and Adolescent Psychiatry 25, 213-220. Cohen,D.J., Towbin,K.E., Mayes,L., and Volkmar,F., 1994. Developmental psychopathology of Multiplex Developmental Disorder. In: S.L. Friedman and H.C. Haywood (Series Ed.), Developmental follow-up: concepts, genres, domains, and methods. New York: Academic Press Inc., pp. 155-179. Combs,D.R., Michael,C.O., and Penn,D.L., 2006. Paranoia and emotion perception across the continuum. The British Journal of Clinical Psychology 45, 19-31. Combs,D.R. and Penn,D.L., 2004. The role of subclinical paranoia on social perception and behavior. Schizophrenia Research 69, 93-104. Cornblatt,B.A., 2000. Continuous Performance Test-Identical Pairs version, release 2.0 [Computer software] New York: Author.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 118

Mirjam Sprong | Adolescents at risk of psychosis Cornblatt,B.A., Lenzenweger,M.F., Dworkin,R.H., and Erlenmeyer-Kimling,L., 1992. Childhood attentional dysfunctions predict social deficits in unaffected adults at risk for schizophrenia. The British Journal of Psychiatry Supplement 18, s59-s64. De Sonneville,L.M., Verschoor,C.A., Njiokiktjien,C., Op,h.V., V, Toorenaar,N., and Vranken,M., 2002. Facial identity and facial emotions: speed, accuracy, and processing strategies in children and adults. Journal of Clinical and Experimental Neuropsychology 24, 200-213. De Sonneville,L.M.J., 2003. Amsterdam Neuropsychological Tasks (ANT) [Manual]. Amstelveen: SONAR. Debbane,M., Glaser,B., David,M.K., Feinstein,C., and Eliez,S., 2006. Psychotic symptoms in children and adolescents with 22q11.2 deletion syndrome: neuropsychological and behavioral implications. Schizophrenia Research 84, 187-193. DeLisi,L.E., Friedrich,U., Wahlstrom,J., Boccio-Smith,A., Forsman,A., Eklund,K., and Crow,T.J., 1994. Schizophrenia and sex chromosome anomalies. Schizophrenia Bulletin 20, 495-505. Dowson,J.H., Sussams,P., Grounds,A.T., and Taylor,J., 2002. Associations of self-reported past "psychotic" phenomena with features of personality disorders. Comprehensive Psychiatry 41, 42-48. Edwards,J., Jackson,H.J., and Pattison,P.E., 2002. Emotion recognition via facial expression and affective prosody in schizophrenia: a methodological review. Clinical Psychology Review 22, 789-832. Francey,S.M., Jackson,H.J., Phillips,L.J., Wood,S.J., Yung,A.R., and McGorry,P.D., 2005. Sustained attention in young people at high risk of psychosis does not predict transition to psychosis. Schizophrenia Research 79, 127-136. Grady,C.L. and Keightley,M.L., 2002. Studies of altered social cognition in neuropsychiatric disorders using functional neuroimaging. Canadian Journal of Psychiatry 47, 327-336. Green,M.F., Kern,R.S., Braff,D.L., and Mintz,J., 2000. Neurocognitive deficits and functional outcome in schizophrenia: are we measuring the "right stuff"? Schizophrenia Bulletin 26, 119-136. Green,M.F., Olivier,B., Crawley,J.N., Penn,D.L., and Silverstein,S., 2005. Social cognition in schizophrenia: recommendations from the measurement and treatment research to improve cognition in schizophrenia new approaches conference. Schizophrenia Bulletin 31, 882-887. Green,M.J., Williams,L.M., and Davidson,D., 2003. Visual scanpaths and facial affect recognition in delusion-prone individuals: increased sensitivity to threat? Cognitive Neuropsychiatry 8, 19-41. Green,M.J., Williams,L.M., and Davidson,D.J., 2001. Processing of threat-related affect is delayed in delusion-prone individuals. The British Journal of Clinical Psychology 40, 157-165.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 119

Mirjam Sprong | Adolescents at risk of psychosis Gross,T.F., 2005. Global-local precedence in the perception of facial age and emotional expression by children with autism and other developmental disabilities. Journal of Autism and Developmental Disorders 35, 773-785. Groth-Marnat,G., 1999. Handbook of psychological assessment (3rd edition). New York: John Wiley & Sons, Inc. Hambrecht,M., Lammertink,M., Klosterkötter,J., Matuschek,E., and Pukrop,R., 2002. Subjective and objective neuropsychological abnormalities in a psychosis prodrome clinic. The British Journal of Psychiatry 181, Supplement 43, s30-s37. Hawkins,K.A., Addington,J., Keefe,R.S., Christensen,B., Perkins,D.O., Zipurksy,R., Woods,S.W., Miller,T.J., Marquez,E., Breier,A., and McGlashan,T.H., 2004. Neuropsychological status of subjects at high risk for a first episode of psychosis. Schizophrenia Research 67, 115-122. Herba,C.M., De Bruin,E., Althaus,M., Verheij,F., and Ferdinand,R.F., 2007. Face and emotion recognition in MCDD versus PDD-NOS. Journal of Autism and Developmental Disorders. Published online August 2007; doi: 10.1007/s10803-007-0438-5. Hobson,R.P., Ouston,J., and Lee,A., 1988. What's in a face? The case of autism. British Journal of Psychology 79, 441-453. Hooker,C. and Park,S., 2002. Emotion processing and its relationship to social functioning in schizophrenia patients. Psychiatry Research 112, 41-50. Howard,M.A., Cowell,P.E., Boucher,J., Broks,P., Mayes,A., Farrant,A., and Roberts,N., 2000. Convergent neuroanatomical and behavioural evidence of an amygdala hypothesis of autism. Neuroreport 11, 29312935. Humphreys,K., Minshew,N., Leonard,G.L., and Behrmann,M., 2007. A fine-grained analysis of facial expression processing in high-functioning adults with autism. Neuropsychologia 45, 685-695. Ihnen,G.H., Penn,D.L., Corrigan,P.W., and Martin,J., 1998. Social perception and social skill in schizophrenia. Psychiatry Research 80, 275-286. Johnstone,E.C., Ebmeier,K.P., Miller,P., Owens,D.G., and Lawrie,S.M., 2005. Predicting schizophrenia: findings from the Edinburgh High-Risk Study. The British Journal of Psychiatry 186, 18-25. Kee,K.S., Horan,W.P., Mintz,J., and Green,M.F., 2004. Do the siblings of schizophrenia patients demonstrate affect perception deficits? Schizophrenia Research 67, 87-94.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 120

Mirjam Sprong | Adolescents at risk of psychosis Kee,K.S., Kern,R.S., and Green,M.F., 1998. Perception of emotion and neurocognitive functioning in schizophrenia: what's the link? Psychiatry Research 81, 57-65. Keefe,R.S., Perkins,D.O., Gu,H., Zipursky,R.B., Christensen,B.K., and Lieberman,J.A., 2006. A longitudinal study of neurocognitive function in individuals at-risk for psychosis. Schizophrenia Research 88, 26-35. Klosterkötter,J., Ruhrmann,S., Schultze-Lutter,F., Salokangas,R.K., Linszen,D., Birchwood,M., Juckel,G., Morrison,A., Vazquez-Barquero,J.L., Hambrecht,M., and Von Reventlow,H., 2005. The European Prediction of Psychosis Study (EPOS): integrating early recognition and intervention in Europe. World Psychiatry 4, 161-167. Kohler,C.G., Bilker,W., Hagendoorn,M., Gur,R.E., and Gur,R.C., 2000. Emotion recognition deficit in schizophrenia: association with symptomatology and cognition. Biological Psychiatry 48, 127-136. Kunugi,H., Lee,K.B., and Nanko,S., 1999. Cytogenetic findings in 250 schizophrenics: evidence confirming an excess of the X chromosome aneuploidies and pericentric inversion of chromosome 9. Schizophrenia Research 40, 43-47. Lencz,T., Smith,C.W., McLaughlin,D., Auther,A., Nakayama,E., Hovey,L., and Cornblatt,B.A., 2006. Generalized and specific neurocognitive deficits in prodromal schizophrenia. Biological Psychiatry 59, 863-871. Lord,C., Rutter,M., and Le Couteur,A., 1994. Autism Diagnostic Interview-Revised (ADI-R): a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. Journal of Autism and Developmental Disorders 24, 659-685. Luna,B., Doll,S.K., Hegedus,S.J., Minshew,N.J., and Sweeney,J.A., 2007. Maturation of executive function in autism. Biological Psychiatry 61, 474-481. Mandal,M.K., Pandey,R., and Prasad,A.B., 1998. Facial expressions of emotions and schizophrenia: a review. Schizophrenia Bulletin 24, 399-412. McGlashan, T. H., Miller, T. J, and Woods, S. W. Structured Interview for Prodromal Syndromes (SIPS) version 3.0, 2001. New Haven: PRIME Research Clinic, Yale School of Medicine. Meyer,J. and Shean,G., 2006. Social-cognitive functioning and schizotypal characteristics. The Journal of Psychology 140, 199-207. Mikhailova,E.S., Vladimirova,T.V., Iznak,A.F., Tsusulkovskaya,E.J., and Sushko,N.V., 1996. Abnormal recognition of facial expression of emotions in depressed patients with major depression disorder and schizotypal personality disorder. Biological Psychiatry 40, 697-705.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 121

Mirjam Sprong | Adolescents at risk of psychosis Miller,T.J., McGlashan,T.H., Woods,S.W., Stein,K., Driesen,N., Corcoran,C.M., Hoffman,R., and Davidson,L., 1999. Symptom assessment in schizophrenic prodromal states. The Psychiatric Quarterly 70, 273-287. Mouridsen,S.E., Rich,B., and Isager,T., 2008. Psychiatric disorders in adults diagnosed as children with atypical autism. A case control study. Journal of Neural Transmission 115, 135-138. Mueser,K.T., Doonan,R., Penn,D.L., Blanchard,J.J., Bellack,A.S., Nishith,P., and DeLeon,J., 1996. Emotion recognition and social competence in chronic schizophrenia. Journal of Abnormal Psychology 105, 271275. Mueser,K.T., Penn,D.L., Blanchard,J.J., and Bellack,A.S., 1997. Affect recognition in schizophrenia: a synthesis of findings across three studies. Psychiatry 60, 301-308. Murphy,K.C., Jones,L.A., and Owen,M.J., 1999. High rates of schizophrenia in adults with velo-cardiofacial syndrome. Archives of General Psychiatry 56, 940-945. Niemi,L.T., Suvisaari,J.M., Tuulio-Henriksson,A., and Lonnqvist,J.K., 2003. Childhood developmental abnormalities in schizophrenia: evidence from high-risk studies. Schizophrenia Research 60, 239-258. Nienow,T.M., Docherty,N.M., Cohen,A.S., and Dinzeo,T.J., 2006. Attentional dysfunction, social perception, and social competence: what is the nature of the relationship? Journal of Abnormal Psychology 115, 408-417. Olsen,K.A. and Rosenbaum,B., 2006. Prospective investigations of the prodromal state of schizophrenia: review of studies. Acta Psychiatrica Scandinavica 113, 247-272. Pelphrey,K.A., Sasson,N.J., Reznick,J.S., Paul,G., Goldman,B.D., and Piven,J., 2002. Visual scanning of faces in autism. Journal of Autism and Developmental Disorders 32, 249-261. Penn,D.L., Corrigan,P.W., Bentall,R.P., Racenstein,J.M., and Newman,L., 1997. Social cognition in schizophrenia. Psychological Bulletin 121, 114-132. Penn,D.L., Spaulding,W., Reed,D., and Sullivan,M., 1996. The relationship of social cognition to ward behavior in chronic schizophrenia. Schizophrenia Research 20, 327-335. Pinkham,A.E. and Penn,D.L., 2006. Neurocognitive and social cognitive predictors of interpersonal skill in schizophrenia. Psychiatry Research 143, 167-178. Pinkham,A.E., Penn,D.L., Perkins,D.O., Graham,K.A., and Siegel,M., 2007. Emotion perception and social skill over the course of psychosis: a comparison of individuals "at-risk" for psychosis and individuals with early and chronic schizophrenia spectrum illness. Cognitive Neuropsychiatry 12, 198-212.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 122

Mirjam Sprong | Adolescents at risk of psychosis Poole,J.H., Tobias,F.C., and Vinogradov,S., 2000. The functional relevance of affect recognition errors in schizophrenia. Journal of the International Neuropsychological Society 6, 649-658. Poreh,A.M., Whitman,R.D., Weber,M., and Ross,T., 1994. Facial recognition in hypothetically schizotypic college students. The role of generalized poor performance. The Journal of Nervous and Mental Disease 182, 503-507. Pukrop,R., Ruhrmann,S., Schultze-Lutter,F., Bechdolf,A., Brockhaus-Dumke,A., and Klosterkötter,J., 2007. Neurocognitive indicators for a conversion to psychosis: comparison of patients in a potentially initial prodromal state who did or did not convert to a psychosis. Schizophrenia Research 92, 116-125. Pukrop,R.,

Schultze-Lutter,F.,

Ruhrmann,S.,

Brockhaus-Dumke,A.,

Tendolkar,I.,

Bechdolf,A.,

Matuschek,E., and Klosterkötter,J., 2006. Neurocognitive functioning in subjects at risk for a first episode of psychosis compared with first- and multiple-episode schizophrenia. Journal of Clinical and Experimental Neuropsychology 28, 1388-1407. Rieffe,C., Meerum,T.M., and Kotronopoulou,K., 2007. Awareness of single and multiple emotions in high-functioning children with autism. Journal of Autism and Developmental Disorders 37, 455-465. Rodriguez Solano,J.J. and Gonzalez,D.C., 2000. Premorbid personality disorders in schizophrenia. Schizophrenia Research 44, 137-144. Rodriguez-Sanchez,J.M., Crespo-Facorro,B., Gonzalez-Blanch,C., Perez-Iglesias,R., and VazquezBarquero,J.L., 2007. Cognitive dysfunction in first-episode psychosis: the processing speed hypothesis. The British Journal of Psychiatry Supplement 51, s107-s110. Sachs,G., Steger-Wuchse,D., Kryspin-Exner,I., Gur,R.C., and Katschnig,H., 2004. Facial recognition deficits and cognition in schizophrenia. Schizophrenia Research 68, 27-35. Schneider,F., Gur,R.C., Gur,R.E., and Shtasel,D.L., 1995. Emotional processing in schizophrenia: neurobehavioral probes in relation to psychopathology. Schizophrenia Research 17, 67-75. Schultze-Lutter,F. and Klosterkötter,J., 2002. Bonn Scale for the Assessment of Basic Symptoms Prediction list (BSABS-P). Cologne: University of Cologne. Seiferth,N.Y., Pauly,K., Habel,U., Kellermann,T., Jon,S.N., Ruhrmann,S., Klosterkotter,J., Schneider,F., and Kircher,T., 2007. Increased neural response related to neutral faces in individuals at risk for psychosis. Neuroimage. Published online November 2007; doi: 10.1016/j.neuroimage.2007.11.020. Serra,M., Althaus,M., De Sonneville,L.M., Stant,A.D., Jackson,A.E., and Minderaa,R.B., 2003. Face recognition in children with a pervasive developmental disorder not otherwise specified. Journal of Autism and Developmental Disorders 33, 303-317.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 123

Mirjam Sprong | Adolescents at risk of psychosis Serra,M., Jackson,A.E., Van Geert,P.L.C., and Minderaa,R.B., 1998. Interpretation of facial expressions, postures and gestures in children with a pervasive developmental disorder not otherwise specified. Journal of Autism and Developmental Disorders 28, 257-263. Shean,G., Bell,E., and Cameron,C.D. (2007). Recognition of nonverbal affect and schizotypy. The Journal of Psychology 141, 281-291. Snitz,B.E., Macdonald,A.W., III, and Carter,C.S., 2006. Cognitive deficits in unaffected first-degree relatives of schizophrenia patients: a meta-analytic review of putative endophenotypes. Schizophrenia Bulletin 32, 179-194. Sprong,M., Becker,H.E., Schothorst,P.F., Swaab,H., Ziermans,T.B., Dingemans,P.M., Linszen,D., and Van Engeland,H., 2008. Pathways to psychosis: a comparison of the pervasive developmental disorder subtype Multiple Complex Developmental Disorder and the "At Risk Mental State". Schizophrenia Research 99, 38-47. Sprong,M., Swaab,H., Becker,H.E., Ziermans,T.B., Dingemans,P.M., Linszen,D., and Van Engeland,H., and Schothorst,P.F. Neurocognitive and behavioral vulnerability markers for psychosis in adolescents at high risk: a comparison of Multiple Complex Developmental Disorder and the "At Risk Mental State". Manuscript submitted for publication. Stahlberg,O., Soderstrom,H., Rastam,M., and Gillberg,C., 2004. Bipolar disorder, schizophrenia, and other psychotic disorders in adults with childhood onset AD/HD and/or autism spectrum disorders. Journal of Neural Transmission 111, 891-902. Swaab-Barneveld,H., de Sonneville,L., Cohen-Kettenis,P., Gielen,A., Buitelaar,J., and Van Engeland,H., 2000. Visual sustained attention in a child psychiatric population. Journal of the American Academy of Child and Adolescent Psychiatry 39, 651-659. Toomey,R. and Schuldberg,D., 1995. Recognition and judgment of facial stimuli in schizotypal subjects. Journal of Communication Disorders 28, 193-203. Toomey,R., Seidman,L.J., Lyons,M.J., Faraone,S.V., and Tsuang,M.T., 1999. Poor perception of nonverbal social-emotional cues in relatives of schizophrenic patients. Schizophrenia Research 40, 121-130. Towbin,K.E., 1997. Pervasive developmental disorder not otherwise specified. In: D.J. Cohen and F.R. Volkmar (Eds.), Handbook of autism and pervasive developmental disorders. Hoboken NJ: John Wiley & Sons, pp. 123-147. Van 't Wout,M., Aleman,A., Kessels,R.P.C., Laroi,F., and Kahn,R.S., 2004. Emotional processing in a nonclinical psychosis-prone sample. Schizophrenia Research 68, 271-281.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 124

Mirjam Sprong | Adolescents at risk of psychosis Van Engeland,H. and Van der Gaag,R.J., 1994. MCDD in childhood: a precursor of schizophrenic spectrum disorders. Schizophrenia Research 11, 197. Van Rijn,S., Aleman,A., Swaab,H., and Kahn,R., 2006. Klinefelter's syndrome (karyotype 47,XXY) and schizophrenia-spectrum pathology. The British Journal of Psychiatry 189, 459-460. Vorstman,J.A., Morcus,M.E., Duijff,S.N., Klaassen,P.W., Heineman-de Boer,J.A., Beemer,F.A., Swaab,H., Kahn,R.S., and Van Engeland,H., 2006. The 22q11.2 deletion in children: high rate of autistic disorders and early onset of psychotic symptoms. Journal of the American Academy of Child and Adolescent Psychiatry 45, 1104-1113. Waldeck,T.L. and Miller,L.S., 2000. Social skills deficits in schizotypal personality disorder. Psychiatry Research 93, 237-246. Wechsler, D., 1997. Wechsler Adult Intelligence Scale-III NL: Afname en scoringshandleiding [Manual]. Psychological Corporation Ltd., Harcourt Publishers. Wechsler, D., 2002. Wechsler Intelligence Scale for Children-III NL: Handleiding en verantwoording [Manual]. Psychological Corporation Ltd., Harcourt Assessment. Whittaker,J.F., Deakin,J.F., and Tomenson,B., 2001. Face processing in schizophrenia: defining the deficit. Psychological Medicine 31, 499-507.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 125

Mirjam Sprong | Adolescents at risk of psychosis

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 126

Mirjam Sprong | Adolescents at risk of psychosis

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 127

Mirjam Sprong | Adolescents at risk of psychosis

Chapter 5

Theory of Mind in schizophrenia: a meta-analysis

Mirjam Sprong a, Patricia Schothorst a, Ellen Vos a, Joop Hox b, Herman van Engeland a The British Journal of Psychiatry (2007), 191: 5-13

a

b

Department of Child and Adolescent Psychiatry, University Medical Centre Utrecht, the Netherlands Faculty of Social Sciences, Department of Methodology & Statistics, Utrecht University, the Netherlands

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 128

Mirjam Sprong | Adolescents at risk of psychosis

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 129

Mirjam Sprong | Adolescents at risk of psychosis

Abstract Background: Mentalising impairment, i.e. an impaired ability to think about people in terms of their mental states, has frequently been associated with schizophrenia. Aims: To assess the magnitude of the deficit and analyse associated factors. Method: Twenty-nine studies of mentalising in schizophrenia (combined n = 1518), published between January 1993 and May 2006, were included to estimate overall effect size. Study descriptors hypothesized to influence effect size were analysed using weighted regression-analysis techniques. Separate analyses were performed for symptom subgroups and task types. Results: The estimated overall effect size was large and statistically significant (d = -1.255, p < .0001) and was not significantly affected by sample characteristics. All symptom subgroups showed significant mentalising impairment, but participants with symptoms of disorganisation were significantly more impaired than the other subgroups (p < .01). Conclusions: This meta-analysis showed significant and stable mentalising impairment in schizophrenia. The finding that patients in remission are also impaired favours the notion that mentalising impairment represents a possible trait marker of schizophrenia. Declaration of interest: None

1. Introduction “Theory of mind” (ToM) and “mentalising” refer to the cognitive ability to attribute mental states such as thoughts, beliefs and intentions to people, allowing an individual to explain, manipulate and predict behaviour. In 1992 Frith proposed a relationship between ToM and schizophrenia, and argued that several symptoms of schizophrenia could be explained by mentalising impairment (Frith 1992). This led to a substantial body of research which has recently been critically reviewed twice (Brüne 2005a; Harrington et al. 2005a). In both reviews it was concluded that ToM is impaired in individuals with schizophrenia. Although these reviews have been executed thoroughly, they are limited to a qualitative description of the observed deficit, thus lacking important information on the magnitude of the effect. The purpose of this meta-analysis is to produce a synthesized effect size estimate that has considerably more power than the individual studies. In addition, effects of study characteristics on the findings are analysed.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 130

Mirjam Sprong | Adolescents at risk of psychosis

2. Method 2.1. Study selection An extensive literature search was conducted in the electronic databases MEDLINE, EMBASE and PsycINFO (January 1993 to May 2006) using the following key words: theory of mind, mentalising, social cognition, schizophrenia, and psychosis. Additional studies were identified by checking the reference lists from identified reviews and papers on the topic. To ensure that we did not overlook studies published by May 2006 but not included in the computerized databases by that date, a journal-by-journal search was performed in the January 2006 to May 2006 editions of The American Journal of Psychiatry, Biological Psychiatry, Journal of Nervous and Mental Disease, Psychiatry Research, Schizophrenia Bulletin, Schizophrenia Research and Psychological Medicine. Studies considered eligible for this meta-analysis were empirical research studies that were written in the English language and published in peer-reviewed journals. Research samples had to be composed of adults diagnosed with schizophrenia or schizoaffective disorder according to the established diagnostic systems (DSM or ICD). Their sample group’s mentalising performance had to be compared with that of healthy controls. Measures of mentalising included in this meta-analysis are described below. Lastly, sufficient data had to be reported for the computation of the standardized mean difference (Lipsey and Wilson 2001).

2.2. Types of mentalising tasks There is a fair amount of agreement on the definition of ToM amongst researchers. However, this definition is broad, perhaps reflecting the fact that it is probably not a unitary function. This has led to a wide variation in the operationalisation of the concept. One of the most frequently used types of mentalising tasks is the false-belief or deception task (e.g. Corcoran et al. 1997; Doody et al. 1998; Frith and Corcoran 1996; Mazza et al. 2001). In a first order false belief/deception task, the ability to understand that someone can hold a belief that is different from the actual state of affairs is assessed. In a second order false belief/deception task, participants have to infer the (false) beliefs of one character about the (false) beliefs of a second character. A second type of ToM task commonly used in schizophrenia research is an intentioninferencing task, in which the ability to infer a character’s intentions from information in a short story is assessed (e.g. Sarfati et al. 1997a, 1997b, 1999, 2000; Sarfati and HardyBayle 1999). A third type of task measures the ability to understand indirect speech such as in irony, banter, hints and metaphors (e.g. Corcoran et al. 1995, Corcoran 2003; Corcoran and Frith 2003; Craig et al. 2004; Langdon et al. 2002a). This is based on the notion that for the understanding of indirect speech an understanding of another person’s mental state

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 131

Mirjam Sprong | Adolescents at risk of psychosis is required (e.g. Sperber and Wilson 2002). However, Langdon & Coltheart (2004) showed that comprehension of irony and comprehension of metaphors are unrelated and that having an intact ToM is a prerequisite for the interpretation of irony but not for the interpretation of metaphors. Therefore, data on the interpretation of metaphors were excluded from this meta-analysis. A fourth, less commonly used type of ToM task in schizophrenia research is the attribution of mental states to animated geometric shapes which interact in a “socially” complex way (Blakemore et al. 2003; Russell et al. 2006). This type of task may not be fully comparable to the other ToM tasks because of the higher level of abstraction that is involved. Finally, in some studies the Eyes Task is used, in which participants have to infer mental states from looking at pictures of eyes (Kelemen et al. 2005; Kington et al. 2000; Russell et al. 2000). This has been referred to as a ToM task, but at face value the construct being measured seems to be different from that assessed by the other paradigms, perhaps assessing emotion recognition abilities or empathy rather than ToM. Since there is a serious lack of research on the psychometric properties (including construct validity and criterion validity) of the many different ToM tasks that have been developed (Harrington et al. 2005a), it may not be possible to formulate completely objective inclusion criteria regarding the type of tasks used in the studies. In this metaanalysis, this problem is addressed statistically in two ways. First, homogeneity analyses are used to check whether the grouping of effect sizes from different studies shows more variation than would be expected from sampling error alone, indicating that the effect sizes may not be comparable. A second approach of this problem is by breaking down the overall mean effect size into mean effect sizes for different types of tasks. For these mean effect sizes per type of task to be meaningful, we (subjectively) set a limit of at least five eligible studies per subtask-analysis. This led to the exclusion of two studies using tasks assessing the attribution of mental states to abstract shapes rather than humans (Blakemore et al. 2003; Russell et al. 2006), and three studies in which the Eyes task was used (Kelemen et al. 2005; Kington et al. 2000; Russell et al. 2000).

2.3. Schizophrenia subgrouping Ever since Frith’s first proposal (Frith 1992), the association between mentalising and the core symptoms of schizophrenia has been an important focus of research interest. Schizophrenia is a heterogeneous disorder and various subgrouping methods have been used, based on different theories regarding the relationship between mentalising and symptomatology. In earlier studies, Frith and colleagues divided their schizophrenia samples into six symptom subgroups (Corcoran et al. 1995). In their later studies, the number of subgroups was reduced to four, categorized as follows:

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 132

Mirjam Sprong | Adolescents at risk of psychosis (a) (b)

behavioural signs of negative symptoms and/or incoherence; paranoid symptoms (delusions of persecution, delusions of reference, and thirdperson hallucinations); (c) passivity experiences (delusions of control, thought insertion, and thought broadcasting); (d) symptoms in remission. The first group was predicted to be the most impaired, because of these patients’ incapacity to represent the mental states of others as well as themselves. Paranoid patients would perform poorly because of their difficulties in monitoring other people’s intentions. Patients whose symptoms were in remission and patients with passivity symptoms were predicted to have normal mentalising abilities. These hypotheses were largely confirmed and have repeatedly been replicated (Corcoran et al. 1997; Frith and Corcoran 1996; Pickup and Frith 2001). Sarfati and colleagues (Sarfati et al. 1997a, 1997b, 1999; Sarfati and Hardy-Bayle 1999) and Zalla et al. (2006) suggested that impairment of ToM is related to thought disorder, reflecting an executive functioning deficit. Thus, their samples were divided in those with and those without thought disorder. In all of their studies thought-disordered participants performed significantly more poorly than healthy controls. However, in two of the studies the non-disorganised subjects also showed poor performance (Sarfati et al. 1997b; Zalla et al. 2006). Three research groups studied the relationship between mentalising and paranoid delusions (Craig et al. 2004; Harrington et al. 2005b; Randall et al. 2003). In all three studies patients with paranoid delusions showed impairment of ToM relative to the normal control group. However, in the study by Randall et al. (2003), ToM performances of the paranoid and non-paranoid subgroups did not significantly differ from each other. Lastly, Herold et al. (2002) investigated whether the deficit in ToM was state- or traitdependent and therefore assessed patients whose schizophrenia was in remission. Results showed that ToM impairment was still present in the remission phase of the illness.

2.4. Moderator variables Published research suggests a number of variables that may affect mentalising performance and thus influence effect size. Hence, we aimed to code these variables in order to evaluate their influence on the effect size. Potential moderator variables at subject level are: age, gender, medication, IQ, disease status (e.g. acute, chronic, or in remission), severity of psychopathology, and symptoms. To analyse the effect of specific clusters of symptoms on mentalising impairment, the different symptom subgroups used by different research groups were divided into four categories:

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 133

Mirjam Sprong | Adolescents at risk of psychosis (a) symptoms of disorganisation; (b) no symptoms of disorganisation; (c) paranoid symptoms; (d) remitted patients. The disorganised subgroup was composed of the behavioural symptoms subgroup of the studies by Frith and colleagues (Corcoran et al. 1995 and 1997; Pickup and Frith 2001) and the disorganised subgroups of the Sarfati, Mazza and Zalla studies (Mazza et al. 2001; Sarfati et al. 1997a, 1997b, 1999; Sarfati and Hardy-Bayle 1999; Zalla et al. 2006). The non-disorganised patients of the Sarfati and Zalla studies were combined into the second subgroup (Sarfati et al. 1997a, 1997b, 1999; Sarfati and Hardy-Bayle 1999; Zalla et al. 2006). For the paranoid subgroup the results of the studies focusing on paranoid schizophrenia (Craig et al. 2004; Harrington et al. 2005b; Randall et al. 2003) were combined with the results for the paranoid subgroups of the studies by Frith and colleagues (Corcoran et al. 1995 and 1997; Pickup and Frith 2001). The remitted subgroup comprised the patients in remission in the studies by Herold et al. (2002), Randall et al. (2003) and Frith and colleagues (Corcoran et al. 1995 and 1997; Pickup and Frith 2001). The passivity subgroup of Frith and colleagues was not coded, because results for that subgroup were reported only in two studies. Potential moderators at study level are the matching of patients and controls on group characteristics (e.g. mean age, mean IQ, gender distribution), type of mentalising task used, and whether the task is administered verbally or non-verbally. Four types of ToM tasks were distinguished: (a) first order false belief/deception; (b) second order false belief/deception; (c) intention inferencing; (d) comprehension of indirect speech. Some tasks did not fit in any of these categories, for example the false belief/deception tasks of which the orders were unknown or mixed. Within the different task-paradigms there is also variation in whether tasks are presented in a verbal or non-verbal form. It has been suggested that verbalisation may be impoverished in schizophrenia and may constitute an experimental bias in favour of a ToM deficit in people with schizophrenia (e.g. Sarfati et al. 1999). In a separate coding, tasks were classified as either verbal or non-verbal.

2.5. Coding Each study was coded independently by two authors (M.S. and E.V.). In case of discrepancies, consensus was reached in conference with the whole research group. When results were reported in graphical form only an e-mail was sent to the author with a request for the exact numerical results.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 134

Mirjam Sprong | Adolescents at risk of psychosis

2.6. Data collection and analysis For each study, an unbiased standardized mean difference (d), was calculated using reported means and standard deviations. This effect size statistic is computed as the difference between the mean of the schizophrenic group and the mean of the control group, divided by the pooled standard deviation. Hedges’ formula was applied to correct for upwardly biased estimation of the effect size in small samples (Lipsey and Wilson 2001). When means and standard deviations were not available, d was calculated from the reported t-or F-values. In cases where the only reported outcome variable was the proportion of participants with a good (or poor) performance, d was estimated using the probit transformation method (Lipsey and Wilson 2001). A sensitivity analysis was performed to check whether there was any significant effect of using probit-transformed effect sizes on the overall effect size. In studies in which data were reported for (symptom) subgroups only, data were first pooled and then compared as one group with the control group. In addition, the effect sizes of symptom subgroups were calculated for subsequent analyses. Several studies used more than one (sub)task to assess ToM, and therefore had more than one effect size. In these cases, a pooled effect size was computed. However, if the authors had included a composite score, the effect size of this score was calculated. Again, effect sizes for different task types were calculated for subsequent analyses. In addition to the individual effect sizes and 95% confidence intervals (CI), P-values were calculated for each study using two-tailed independent t-tests and χ 2 -tests. The mean effect size across studies was calculated by weighting each effect size by the inverse of its sampling variance. A confidence interval and z-value were calculated to examine the statistical significance of the effect. To test whether the individual effect sizes are good estimators of the population effect size, the homogeneity statistic Q was calculated (Lipsey and Wilson 2001). Because sample sizes are small in the subgroup and task type analyses (see below), a random effects model was fitted to the data (Lipsey and Wilson 2001). To examine publication bias, a fail-safe number was computed using Orwin’s formula (Lipsey and Wilson 2001). This indicates the number of studies with null effects that has to reside in file drawers to reduce the mean effect size to a negligible level (which we set at 0.2). Weighted regression analysis was performed using the statistical package Meta-Stat (Rudner et al. 2002) to evaluate whether group differences in IQ, gender and age affected effect size. Other variables with a potential influence on effect size, such as patient status, medication use and severity of psychopathology could not be analysed, because of the small number of studies reporting results for these parameters. Separate analyses were performed to analyse whether mentalising impairment is different for different symptom subgroups or for different types of mentalising tasks.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 135

Mirjam Sprong | Adolescents at risk of psychosis

3. Results 3.1. Literature search results The literature search resulted in a total of 32 studies meeting the inclusion criteria. One publication (Langdon et al. 2002a) was excluded because data concerning the same participants had been reported in another publication (Langdon et al. 2002b). Patient characteristics (i.e. n, mean age, % males, mean score on Binois-Pichot Vocabulary Scale, and mean score on the nonverbal ToM test) were exactly the same in two studies by Sarfati and colleagues (Sarfati et al. 2000; Sarfati and Hardy-Bayle 1999), suggesting that the same patient samples had been used. Because in the first of these studies the patient sample was divided into symptom subgroups, but more controls and an additional ToM task were used in the latter study, instead of selecting one of the two studies, the results of these studies were combined. Because we were unable to contact the authors of one study within the time frame of data collection and data analysis to obtain the exact numerical results which were not reported in the article, the results of that study could not be included in the meta-analysis (Frith and Corcoran 1996). The characteristics of the remaining 29 studies with a total of 831 patients (mean age 35.9 years, 70% male, mean IQ 98.7) and 687 controls (mean age 35.2 years, 60% male, mean IQ 105.3) are listed in Table 1.

3.2. Analysis of the total sample Figure 1 shows the 29 individual effect sizes with their 95% CIs. None of the CIs includes the value zero, indicating a statistically significant effect for each study. The weighted mean effect size of the combined sample is -1.255 (95% CI: -1.441 to -1.069) which is also statistically significant (z =13.25, p < .0001). Homogeneity analysis showed that there was homogeneity among studies (Q = 29.13, df = 28, p = 0.41), and weighted regression analysis did not show any relationship between effect size and difference between patient and control groups in IQ (p = .193), proportion of males (p = .115) and age (p = .147). The fail-safe number was 153, which indicates that 153 unpublished studies with null effects are required to reduce the effect size of the combined findings to a negligible level.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 136

Mirjam Sprong | Adolescents at risk of psychosis

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 137

Mirjam Sprong | Adolescents at risk of psychosis Continued

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 138

Mirjam Sprong | Adolescents at risk of psychosis Continued

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 139

Mirjam Sprong | Adolescents at risk of psychosis Continued

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 140

Mirjam Sprong | Adolescents at risk of psychosis Figure 1. Individual and mean effect sizes (d) and 95% confidence intervals of mentalising deficits in schizophrenia

3.3. Analyses of the symptom subgroups Mean effect sizes and 95% CIs of the symptom subgroups are displayed in Figure 2. The disorganised patients performed worst on the mentalising tasks compared with healthy controls (d = -2.231, 95% CI: -2.565 to -1.897, p < .01). The CI of the mean effect size in the disorganised subgroup shows no overlap with that in the non-disorganised (d = 1.278, 95% CI: -1.771 to -0.785, p < .01) and the paranoid subgroups (d = -1.241, 95% CI: -1.514 to -0.968, p < .01), indicating that the difference between the disorganised subgroup and the other subgroups is statistically significant. This was confirmed by post hoc comparisons of the mean effect size of the disorganised subgroups versus the mean effect sizes of the other three symptom subgroups (all pvalues < .01). Interestingly, remitted patients also showed a significantly worse performance than controls (d = -0.692, 95% CI: -1.017 to -0.367, p < .01). The homogeneity statistic of the non-disorganised subgroup was statistically significant

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 141

Mirjam Sprong | Adolescents at risk of psychosis (Q = 7.3816, df = 4, p < .05), indicating that the effect sizes within this subgroup analysis differed more than would be expected from sampling error alone, perhaps owing to differences associated with study (or sample) characteristics. This was somewhat surprising, since four of the five studies were by the same research group. The finding that the other three homogeneity statistics were not statistically significant suggests that although different authors might have used different criteria for their symptom subgroups, combining these subgroups was meaningful. Figure 2. Mean effect sizes (d) and 95% confidence intervals of mentalising deficits in symptom subgroups of schizophrenia

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 142

Mirjam Sprong | Adolescents at risk of psychosis Figure 3. Mean effect sizes (d) and 95% confidence intervals of mentalising deficits for different types of mentalising tasks

Note. 1st order = first order false belief and deception tasks 2nd order = second order false belief and deception tasks speech = tasks assessing the comprehension of indirect speech intention = intention-inferencing tasks

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 143

Mirjam Sprong | Adolescents at risk of psychosis

3.4. Analyses of the types of mentalising tasks The mean effect sizes and 95% CIs of the four ToM task categories are shown in Figure 3. The mean effect sizes of the first-order tasks (d = -1.193, 95% CI: -1.666 to -0.720, p < .01) and the second-order tasks (d = -1.443, 95% CI: -1.867 to -1.019, p < .01) have homogeneity statistics indicating heterogeneity among the effect sizes (Q = 97.691, df = 12, p < .01, and Q = 17.875, df = 6, p < .01 respectively). In contrast, the mean effect sizes within both the indirect speech tasks (d =-1.040, 95% CI: -1.301 to 0.779, p < .01) and the intention-inferencing tasks (d = -0.959, 95% CI: -1.228 to 0.690, p < .01) are both homogeneous. The difference between the mean effect sizes for different subtasks could not be analysed statistically, because not all effect sizes are statistically independent since in one study different types of tasks may have been used. The mean effect size of studies using verbal tasks is comparable to the mean effect size of studies using non-verbal tasks (verbal d = -1.221, 95% CI: -1.462 to -0.980; nonverbal d = -1.251, 95% CI: -1.496 to -1.006). The homogeneity statistics of the verbal and the non-verbal tasks both show heterogeneity among the effect sizes. Again, the difference could not be analysed because of statistical dependence.

4. Discussion The aim of this meta-analysis was to investigate the extent of mentalising impairment in people with schizophrenia. By combining 29 studies, a total sample size was created of over 1500 subjects. The overall effect size was -1.1255, indicating that on average the ToM performance of people with schizophrenia is more than one standard deviation below that of healthy controls. According to a widely used convention for appraising the magnitude of effect sizes this is considered a large effect (Cohen 1988). Homogeneity analysis showed that the mean effect size of the combined samples is a good estimate of the typical effect size in the population. The large fail-safe number makes the file drawer problem, which is a limitation of some meta-analyses, negligible. The moderator variables IQ, gender, and age did not significantly affect mean effect size. Thus, the impairment in ToM is robust and not readily moderated by variables that may seem relevant. However, the effect of other potentially important moderator variables such as medication use, duration and severity of the illness could not be analysed owing to a lack of information on these characteristics in many studies. Participants with schizophrenia who had signs and symptoms of disorganisation were found to be significantly more impaired in terms of ToM than those in the other symptom subgroups. However, these results may also be explained by the composition of the disorganised symptom subgroup. The behavioural subgroup of the studies by Frith and colleagues is ranked highest in their hierarchical model. Thus, these individuals in this group may also have had symptoms of the paranoid and/or passivity subgroup.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 144

Mirjam Sprong | Adolescents at risk of psychosis This brings the risk that poorer performance in this group may be explained by having more severe and complex symptomatology (Harrington et al. 2005a). Similarly, in two of the four studies by Sarfati and colleagues the disorganised subgroup had more general psychopathology, which might explain their poorer ToM performance (Sarfati et al. 1999; Sarfati and Hardy-Bayle 1999). The mean effect size (d = -0.692) of mentalising impairment in patients in remission was smaller than in the other symptom subgroups, but is still considered to be medium to large (Cohen 1988). Moreover, this effect did not differ significantly from the effect sizes of the difference with the non-disorganised and paranoid subgroups. Unexpectedly - and despite apparent differences in type and difficulty of the types of ToM tasks - the mean effect sizes for different task types were found to be similar. An explanation might be that the employed method of grouping studies by task types was not correct. This is supported by the finding that two of the four task type analyses showed heterogeneity amongst effect sizes. However, since there is a lack of research on the psychometric properties of the tasks that were used, such as construct and concurrent validity, it is not yet possible to categorise these tasks objectively. There was also no difference between the mean effect sizes of verbal and nonverbal tasks, which is consistent with the findings of Sarfati and colleagues (Sarfati et al. 1999 and 2000). Thus, impairment of ToM does not to appear to be affected by the verbalisation deficits that have been reported in people with schizophrenia.

4.1. Mentalising in schizophrenia: generalised versus specific impairment As shown in the famous meta-analysis by Heinrichs & Zakzanis (1998), people with schizophrenia show generalised neurocognitive impairment. On their list of 22 mean effect sizes of common neurocognitive tests, the effect size of mentalising impairment would be ranked fourth. An interesting question is, whether poor mentalising performance in schizophrenia interacts with, or is influenced by general cognitive impairment. This problem is acknowledged by some authors, who corrected for general cognitive abilities by matching groups on IQ, covarying out cognitive variables (e.g. attention, executive functioning, memory, general picture sequencing abilities), or excluding participants from statistical analyses if they answered reality questions about the ToM stories incorrectly. In their reviews, Brüne (2005a, p. 25) and Harrington et al. (2005a, p. 252-267) discuss the empirical evidence as to whether the mentalising deficits in schizophrenia are specific or the consequence of general cognitive impairment. In both reviews it was concluded that the evidence speaks in favour of the notion that there is a specific ToM deficit in schizophrenia. As with many neurocognitive tests, ToM tasks probably measure several component processes at the same time. For example, tasks in which the comprehension of indirect speech is assessed may not only require mentalising abilities, but also basic language comprehension and expressive

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 145

Mirjam Sprong | Adolescents at risk of psychosis language skills. Possibly, general cognitive abilities represent a necessary but not sufficient condition for adequate mentalising, which is known as the “building block view” of social cognition (in: Penn et al. 1997).

4.2. Mentalising in schizophrenia: state or trait dependency In his cognitive model of the relationship between meta-representation and the signs and symptoms of schizophrenia, Frith assumed that in people with this disorder, the initial development of mentalising abilities is relatively normal and that these abilities become impaired as illness develops (Frith 1992). In the subsequent studies by him and his colleagues, it was predicted and found that patients who were in remission (i.e. symptom-free) are unimpaired compared with normal controls (e.g. Corcoran et al. 1995 and 1997; Frith and Corcoran 1996; Pickup and Frith 2001). In contrast, our metaanalysis has shown that patients also show significant impairment during remission, which is consistent with the findings by Herold et al. (2002). These findings support the notion that mentalising is not just a consequence of the acute phase of the disorder, but may be trait-dependent. It cannot be excluded that the criteria for remission (e.g. partial or full remission) used by Herold et al. (2002) and by Frith and colleagues are different. Other factors, such as (prophylactic) treatment may also explain the divergent findings. However, more support for the trait argument comes from studies on mentalising in populations at elevated risk for developing a psychotic illness. In general, people at genetic risk for schizophrenia show reduced performance on the more common types of ToM tasks (Irani et al. 2006; Marjoram et al. 2006; Wykes et al. 2001), but not on the Eyes Test (Irani et al. 2006; Kelemen et al. 2004). In the study by Schiffman et al. (2004), genetic high-risk children who would later develop schizophrenia-spectrum disorders had lower scores on a role-Taking Task, which the authors considered assessed a facet of ToM. An association between ToM performance and subclinical schizotypal traits has also been found (Irani et al. 2006; Langdon and Coltheart 1999 and 2004; Meyer and Shean 2006). Pickup (2006) showed that schizotypal traits analogous to positive symptoms of schizophrenia predicted poorer mentalising performance, whereas no association was found between poorer ToM and schizotypal traits analogous to the "behavioural signs" of schizophrenia. Platek et al. (2003) suggested that contagious yawning is part of a more general phenomenon known as mental state attribution. Consistent with this hypothesis, susceptibility to contagious yawning was positively related to performance on (other) mentalising tasks, and negatively related to schizotypal personality traits. Only in the study by Jahshan & Sergi (2007) there was no difference between people with high schizotypy versus those with low schizotypy regarding ToM performance. Thus, there is considerable evidence that mentalising impairment is a susceptibility indicator for schizophrenia and hence may be trait-dependent.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 146

Mirjam Sprong | Adolescents at risk of psychosis

4.3. Limitations The first limitation, to which we have already alluded, is that studies were excluded in which less common types of ToM tasks were used. Because there is no information on the psychometric properties of the many different tasks, this is somewhat arbitrary. In addition, the categorisation of task type is not supported by psychometric evidence. Second, the method of categorising symptom subgroups employed in this meta-analysis should be considered tentative. The main problem with our approach is that there is overlap between symptom clusters. For example, the subgrouping method used by Frith and colleagues is hierarchical, with the behavioural subgroup being the highest category. This means that patients in that subgroup could also report paranoid symptoms, but those in the paranoid subgroup could not report behavioural symptoms. As another example, participants categorised as paranoid in the study by Harrington et al. (2005b) could also have formal thought disorder (which was indeed the case). However, in spite of this limitation, we still believe the results of the subgroup analyses in these meta-analysis are valuable. This is statistically supported by the homogeneity analyses, which show that the clustering of symptom subgroups did not result in more variation than would be expected from sampling error alone and that it is plausible that the studies within the subgroup analyses are comparable.

4.4. Recommendations for future research The results and limitations of this meta-analysis lead to some recommendations for future research. First, research focusing on the mentalising process itself is necessary, addressing questions on what components it comprises and on how to operationalise them. As has already been pointed out by Harrington et al. (2005a), it is also important to establish the psychometric properties of ToM tasks. Second, the finding that the deficit in ToM schizophrenia is perhaps trait-dependent rather than state-dependent implies that the deficit may also be present before illness onset. Therefore, there may be a role of mentalising impairment in the early detection and prediction of schizophrenia, requiring a longitudinal study examining ToM abilities in people at risk of developing schizophrenia. Third, the finding that ToM impairment may be trait-dependent also brings to mind a comparison with autism-spectrum disorders. An impaired ability to understand mental states has been described as one of the core symptoms of such disorders (Yirmiya et al. 1998). However, although the risk of psychotic disorders is elevated in individuals with autism-spectrum disorders (Stahlberg et al. 2004), most of them will not develop a psychotic disorder. Future research should focus on what the commonalities and differences are with regard to ToM in these disorders. Abu-Akel & Bailey (2000) for example suggested that there might be different forms of impairment of ToM. They argue that, unlike people with autism-spectrum disorders, people with schizophrenia do

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 147

Mirjam Sprong | Adolescents at risk of psychosis not lack an understanding that others have mental states. Instead, they may overattribute knowledge to others or apply their knowledge of mental states in an incorrect or biased way. Thus, an interesting research topic would be the comparison of the mentalising abilities of groups of people with these two disorders. Lastly, social impairment is one of the most disabling clinical features of schizophrenia and it is well known that it is often present before illness onset (e.g. Niemi et al. 2003). Since ToM impairment appears to be trait- rather than state-dependent in schizophrenia, this deficit may have a role in the development of social impairment. However, evidence of a relationship between ToM performance and social functioning is lacking and should be an aim of future research.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 148

Mirjam Sprong | Adolescents at risk of psychosis

References Abu-Akel,A. and Bailey,A.L., 2000. The possibility of different forms of theory of mind impairment in psychiatric and developmental disorders. Psychological Medicine 30, 735-738. Blakemore,S.J., Sarfati,Y., Bazin,N., and Decety,J., 2003. The detection of intentional contingencies in simple animations in patients with delusions of persecution. Psychological Medicine, 1433-1441. Brüne,M., 2003. Theory of mind and the role of IQ in chronic disorganised schizophrenia. Schizophrenia Research 60, 57-64. Brüne,M., 2005a. "Theory of mind" in schizophrenia: a review of the literature. Schizophrenia Bulletin 31, 21-42. Brüne,M., 2005b. Emotion recognition, 'theory of mind,' and social behavior in schizophrenia. Psychiatry Research 133, 135-147. Brüne,M. and Bodenstein,L., 2005. Proverb comprehension reconsidered--'theory of mind' and the pragmatic use of language in schizophrenia. Schizophrenia Research 75, 233-239. Brunet,E., Sarfati,Y., Hardy-Bayle,M.C., and Decety,J., 2003a. Abnormalities of brain function during a nonverbal theory of mind task in schizophrenia. Neuropsychologia 41, 1574-1582. Brunet,E., Sarfati,Y., and Hardy-Bayle,M.C., 2003b. Reasoning about physical causality and other's intentions in schizophrenia. Cognitive Neuropsychiatry 8, 129-139. Cohen,J., 1988. Statistical power analysis for the behavioral sciences (2nd edition). Hillsdale NJ: Erlbaum. Corcoran,R., 2003. Inductive reasoning and the understanding of intention in schizophrenia. Cognitive Neuropsychiatry 8, 223-235. Corcoran,R. and Frith,C.D., 2003. Autobiographical memory and theory of mind: evidence of a relationship in schizophrenia. Psychological Medicine 33, 897-905. Corcoran,R., Mercer,G., and Frith,C.D., 1995. Schizophrenia, symptomatology and social inference: investigating "theory of mind" in people with schizophrenia. Schizophrenia Research 17, 5-13. Corcoran,R., Cahill,C., and Frith,C.D., 1997. The appreciation of visual jokes in people with schizophrenia: a study of 'mentalising' ability. Schizophrenia Research 24, 319-327.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 149

Mirjam Sprong | Adolescents at risk of psychosis Craig,J.S., Hatton,C., Craig,F.B., and Bentall,R.P., 2004. Persecutory beliefs, attributions and theory of mind: comparison of patients with paranoid delusions, Asperger's syndrome and healthy controls. Schizophrenia Research 69, 29-33. Doody,G.A., Gotz,M., Johnstone,E.C., Frith,C.D., and Owens,D.G., 1998. Theory of mind and psychoses. Psychological Medicine 28, 397-405. Frith,C.D., 1992. The cognitive neuropsychology of schizophrenia. Hove: Psychology Press. Frith,C.D. and Corcoran,R., 1996. Exploring 'theory of mind' in people with schizophrenia. Psychological Medicine 26, 521-530. Harrington,L., Siegert,R.J., and McClure,J., 2005a. Theory of mind in schizophrenia: a critical review. Cognitive Neuropsychiatry 10, 249-286. Harrington,L., Langdon,R., Siegert,R.J., and McClure,J., 2005b. Schizophrenia, theory of mind, and persecutory delusions. Cognitive Neuropsychiatry 10, 87-104. Heinrichs,R.W. and Zakzanis,K.K., 1998. Neurocognitive deficit in schizophrenia: a quantitative review of the evidence. Neuropsychology 12, 426-445. Herold,R., Tenyi,T., Lenard,K., and Trixler,M., 2002. Theory of mind deficit in people with schizophrenia during remission. Psychological Medicine 32, 1125-1129. Irani,F., Platek,S.M., Panyavin,I.S., Calkins,M.E., Kohler,C., Siegel,S.J., Schachter,M., Gur,R.E., and Gur,R.C., 2006. Self-face recognition and theory of mind in patients with schizophrenia and first-degree relatives. Schizophrenia Research 88, 151-160. Jahshan,C.S. and Sergi,M.J., 2007. Theory of mind, neurocognition, and functional status in schizotypy. Schizophrenia Research 89, 278-286. Janssen,I., Krabbendam,L., Jolles,J., and Van Os,J., 2003. Alterations in theory of mind in patients with schizophrenia and non-psychotic relatives. Acta Psychiatrica Scandinavica 108, 110-117. Kelemen,O., Keri,S., Must,A., Benedek,G., and Janka,Z., 2004. No evidence for impaired 'theory of mind' in unaffected first-degree relatives of schizophrenia patients. Acta Psychiatrica Scandinavica 110, 146149. Kelemen,O., Erdelyi,R., Pataki,I., Benedek,G., Janka,Z., and Keri,S., 2005. Theory of mind and motion perception in schizophrenia. Neuropsychology 19, 494-500.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 150

Mirjam Sprong | Adolescents at risk of psychosis Kington,J.M., Jones,L.A., Watt,A.A., Hopkin,E.J., and Williams,J., 2000. Impaired eye expression recognition in schizophrenia. Journal of Psychiatric Research 34, 341-347. Langdon,R. and Coltheart,M., 1999. Mentalising, schizotypy, and schizophrenia. Cognition 71, 43-71. Langdon,R. and Coltheart,M., 2001. Mentalising, executive planning and disengagement in schizophrenia. Cognitive Neuropsychiatry 6, 81-108. Langdon,R. and Coltheart,M., 2004. Recognition of metaphor and irony in young adults: the impact of schizotypal personality traits. Psychiatry Research 125, 9-20. Langdon,R., Michie,P.T., Ward,P.B., McConaghy,N., Catts,S.V., and Coltheart,M., 1997. Defective Self and/or Other mentalising in schizophrenia: a cognitive neuropsychological approach. Cognitive Neuropsychiatry 2, 167-193. Langdon,R., Davies,M., and Coltheart,M., 2002a. Understanding minds and understanding communicated meanings in schizophrenia. Mind and Language 17, 68-104. Langdon,R., Coltheart,M., Ward,P.B., and Catts,S.V., 2002b. Disturbed communication in schizophrenia: the role of poor pragmatics and poor mind-reading. Psychological Medicine 32, 1273-1284. Langdon,R., Coltheart,M., and Ward,P.B., 2006. Empathetic perspective-taking is impaired in schizophrenia: evidence from a study of emotion attribution and theory of mind. Cognitive Neuropsychiatry 11, 133-155. Lipsey,M.W. and Wilson,D.B., 2001. Practical Meta-Analysis. Thousand Oaks CA: Sage Publications, Inc. Marjoram,D., Tansley,H., Miller,P., MacIntyre,D., Owens,D.G., Johnstone,E.C., and Lawrie,S., 2005a. A theory of mind investigation into the appreciation of visual jokes in schizophrenia. BMC Psychiatry 5, 12. Marjoram,D., Gardner,C., Burns,J., Miller,P., Lawrie,S.M., and Johnstone,E.C., 2005b. Symptomatology and social inference: a theory of mind study of schizophrenia and psychotic affective disorder. Cognitive Neuropsychiatry 10, 347-359. Marjoram,D., Miller,P., McIntosh,A.M., Cunningham Owens,D.G., Johnstone,E.C., and Lawrie,S., 2006. A neuropsychological investigation into 'Theory of Mind' and enhanced risk of schizophrenia. Psychiatry Research 144, 29-37. Mazza,M., De Risio,A., Surian,L., Roncone,R., and Casacchia,M., 2001. Selective impairments of theory of mind in people with schizophrenia. Schizophrenia Research 47, 299-308.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 151

Mirjam Sprong | Adolescents at risk of psychosis Mazza,M., De Risio,A., Tozzini,C., Roncone,R., and Casacchia,M., 2003. Machiavellianism and Theory of Mind in people affected by schizophrenia. Brain and Cognition 51, 262-269. Meyer,J. and Shean,G., 2006. Social-cognitive functioning and schizotypal characteristics. Journal of Psychology 140, 199-207. Niemi,L.T., Suvisaari,J.M., Tuulio-Henriksson,A., and Lonnqvist,J.K., 2003. Childhood developmental abnormalities in schizophrenia: evidence from high-risk studies. Schizophrenia Research 60, 239-258. Penn,D.L., Corrigan,P.W., Bentall,R.P., Racenstein,J.M., and Newman,L., 1997. Social cognition in schizophrenia. Psychological Bulletin 121, 114-132. Pickup,G.J., 2006. Theory of mind and its relation to schizotypy. Cognitive Neuropsychiatry 11, 177-192. Pickup,G.J. and Frith,C.D., 2001. Theory of mind impairments in schizophrenia: symptomatology, severity and specificity. Psychological Medicine 31, 207-220. Platek,S.M., Critton,S.R., Myers,T.E., and Gallup,G.G., 2003. Contagious yawning: the role of selfawareness and mental state attribution. Brain Research and Cognitive Brain Research 17, 223-227. Randall,F., Corcoran,R., Day,J.C., and Bentall,R.P., 2003. Attention, theory of mind, and causal attributions in people with persecutory delusions: a preliminary investigation. Cognitive Neuropsychiatry 8, 287-294. Rudner, L. M., Glass, G. V., Evartt, D. L., and Emery, P. J., 2002. Meta-Stat - A user's guide to the metaanalysis of research studies. ERIC Clearinghouse on Assessment and Evaluation, Department of Measurement, Statistics and Evaluation, University of Maryland (http://www.edres.org/meta). Russell,T.A., Rubia,K., Bullmore,E.T., Soni,W., Suckling,J., Brammer,M.J., Simmons,A., Williams,S.C., and Sharma,T., 2000. Exploring the social brain in schizophrenia: left prefrontal underactivation during mental state attribution. The American Journal of Psychiatry 157, 2040-2042. Russell,T.A., Reynaud,E., Herba,C., Morris,R., and Corcoran,R., 2006. Do you see what I see? Interpretations of intentional movement in schizophrenia. Schizophrenia Research 81, 101-111. Sarfati,Y. and Hardy-Bayle,M.C., 1999. How do people with schizophrenia explain the behaviour of others? A study of theory of mind and its relationship to thought and speech disorganisation in schizophrenia. Psychological Medicine 29, 613-620. Sarfati,Y., Hardy-Bayle,M.C., Besche,C., and Widlocher,D., 1997a. Attribution of intentions to others in people with schizophrenia: a non-verbal exploration with comic strips. Schizophrenia Research 25, 199209.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 152

Mirjam Sprong | Adolescents at risk of psychosis Sarfati,Y., Hardy-Bayle,M.C., Nadel,J., Chevalier,J., and Widlocher,D., 1997b. Attribution of mental states to others by schizophrenic patients. Cognitive Neuropsychiatry 2, 1-17. Sarfati,Y., Hardy-Bayle,M.C., Brunet,E., and Widlocher,D., 1999. Investigating theory of mind in schizophrenia: influence of verbalization in disorganised and non-disorganised patients. Schizophrenia Research 37, 183-190. Sarfati,Y., Passerieux,C., and Hardy-Bayle,M., 2000. Can verbalization remedy the theory of mind deficit in schizophrenia? Psychopathology 33, 246-251. Schiffman,J., Lam,C.W., Jiwatram,T., Ekstrom,M., Sorensen,H., and Mednick,S., 2004. Perspective-taking deficits in people with schizophrenia spectrum disorders: a prospective investigation. Psychological Medicine 34, 1581-1586. Sperber,D. and Wilson,D., 2002. Pragmatics, modularity and mind-reading. Mind and Language. 17, 323. Stahlberg,O., Soderstrom,H., Rastam,M., and Gillberg,C., 2004. Bipolar disorder, schizophrenia, and other psychotic disorders in adults with childhood onset AD/HD and/or autism spectrum disorders. Journal of Neural Transmission 111, 891-902. Wykes,T., Hamid,S., and Wagstaff,K., 2001. Theory of mind and executive functions in the non-psychotic siblings of patients with schizophrenia. Schizophrenia Research 49, 148. Yirmiya,N., Erel,O., Shaked,M., and Solomonica-Levi,D., 1998. Meta-analyses comparing theory of mind abilities of individuals with autism, individuals with mental retardation, and normally developing individuals. Psychological Bulletin 124, 283-307. Zalla,T., Bouchilloux,N., Labruyere,N., Georgieff,N., Bougerol,T., and Franck,N., 2006. Impairment in event sequencing in disorganised and non-disorganised patients with schizophrenia. Brain Research Bulletin 68, 195-202.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 153

Mirjam Sprong | Adolescents at risk of psychosis

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 154

Mirjam Sprong | Adolescents at risk of psychosis

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 155

Mirjam Sprong | Adolescents at risk of psychosis

Correspondence

The British Journal of Psychiatry (2008), 192: 312–315

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 156

Mirjam Sprong | Adolescents at risk of psychosis

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 157

Mirjam Sprong | Adolescents at risk of psychosis

Mentalising impairment as a trait marker of schizophrenia? Esther Pousa, Ada I. Ruiz, Anthony S. David One of the most controversial issues in Theory of Mind research in schizophrenia in recent years has been whether theory of mind impairment may be seen as a trait marker or rather linked to particular symptoms. Sprong et al. (2007) conclude that evidence to date seems to favor the notion that mentalising impairment represents a possible trait marker. We believe that their meta-analysis is an excellent piece of scientific work but that this conclusion should remain tentative. First, the existing evidence on theory of mind abilities in remitted patients is limited and difficult to interpret because of methodological shortcomings, such as non-explicit criteria for remission and poor control of cognitive abilities in the experimental design. A recent study by our group (Pousa et al. 2008) revealed that as a whole, stable patients did not show theory of mind impairment compared with carefully matched nonpsychiatric controls. When standard consensus criteria for remission were applied to the sample, half failed to meet criteria for remission and showed a significantly worse theory of mind performance than remitted patients and controls. Specific theory of mind deficits in this group were associated with delusions. Thus, specific theory of mind impairment could go hand-in-hand with the presence of symptoms. Second, findings of theory of mind impairment in schizophrenia high-risk groups seem to support the assumption that theory of mind deficits represent a trait marker of the disorder. However, since these studies are mostly correlational, it is possible that the continuity of theory of mind deficits among “at risk” groups may in fact derive from an intrinsic relationship between a psychotic symptoms continuum and theory of mind impairment. A review of the literature of theory of mind and schizotypal personality traits reveals that studies finding a positive significant relationship do so mainly with respect to schizotypal positive traits such as the cognitive-perceptual and unusual experiences dimensions of the schizotypy instruments (Pickup 2006). Regarding investigations of first-degree relatives, evidence is controversial (Sprong et al. 2007), with findings of impaired performance on the more common types of theory of mind tasks but not on the ‘eyes’ test. However, it should be noted from these studies that those controlling for subclinical symptoms or schizotypal traits conclude that the association may be linked exclusively to the presence of subclinical positive symptoms (Irani et al. 2006; Marjoram et al. 2006). In our opinion, the existing evidence in theory of mind research is still limited but the possibility of a state-like association should not be ruled out. The most methodologically sound means to explore this would be to carry out longitudinal studies comparing theory of mind abilities in different phases of the illness, defined by explicit criteria. Future studies also need to differentiate between the affective and cognitive aspects of

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 158

Mirjam Sprong | Adolescents at risk of psychosis theory of mind, since it is possible that these show a different pattern of relationship with symptom clusters or schizophrenia profiles. Furthermore, it is possible that future research reveals that state-trait interactions may be occurring.

References Irani,F., Platek,S.M., Panyavin,I.S., Calkins,M.E., Kohler,C., Siegel,S.J., Schachter,M., Gur,R.E., Gur,R.C., 2006. Self-face recognition and theory of mind in patients with schizophrenia and first-degree relatives. Schizophrenia Research 88, 151-160. Marjoram,D., Miller,P., McIntosh,A.M., Cunningham Owens,D.G., Johnstone,E.C., Lawrie,S., 2006. A neuropsychological investigation into ’Theory of Mind’ and enhanced risk of schizophrenia. Psychiatry Research 144, 29-37. Pickup,G.J., 2006. Theory of mind and its relation to schizotypy. Cognitive Neuropsychiatry 11, 177-192. Pousa,E., DuÀó,R., Brébion,G., David,A.S., Ruiz,A.I., Obiols,J.E., 2008. Theory of mind deficits in chronic schizophrenia: evidence for state dependence. Psychiatry Research 158, 1-10. Sprong,M., Schothorst,P., Vos,E., Hox,J., Van Engeland,H., 2007. Theory of mind in schizophrenia: metaanalysis. The British Journal of Psychiatry 191, 5-13.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 159

Mirjam Sprong | Adolescents at risk of psychosis

Authors’ reply Mirjam Sprong, Patricia Schothorst, Ellen Vos, Joop Hox, Herman van Engeland Pousa et al. comment that our conclusion that theory of mind impairment represents a possible trait marker for schizophrenia should remain tentative for two reasons. Regarding their first argument, data on remitted patients are indeed limited and have methodological shortcomings. Only five studies in remitted patients were available, and the number of remitted patients in each of these studies was small. We also remarked that the criteria for remission used may have varied across studies, and that other factors may have influenced the results. Thus, we agree that the conclusion that theory of mind impairment represents a trait marker for schizophrenia should be tentative. In fact, we did describe it as a ‘possible’ trait marker. It is important to note that meta-analyses are about effect sizes rather than significance levels. By synthesizing data of multiple studies there is more statistical power to detect smaller group differences. Thus, although in three out of five studies the theory of mind impairment in remitted patients was not statistically significant, when the studies were combined, the overall effect was significant (mean d = 70.692, P < 0.01). So when Pousa et al. do no find theory of mind impairment in stable remitted patients, we are not only interested in the P-levels, but also in the effect size. We also agree with the second point that there is evidence of an association between psychotic symptoms and theory of mind impairment, but do not see why this would argue against our conclusion. Frith (1992) already proposed associations between specific schizophrenia symptoms (e.g. paranoid delusions) and mentalising impairment, and in their upcoming paper Pousa et al. apparently also find significant associations between theory of mind impairment and psychotic symptoms. Perhaps we should have stated that theory of mind impairment is a possible trait marker for psychosis rather than schizophrenia. We believe that theory of mind probably does not represent an ‘all or nothing’ skill, and that schizophrenia should perhaps be studied using a dimensional instead of a categorical approach.

Reference Frith,C.D., 1992. The cognitive neuropsychology of schizophrenia. Hove: Psychology Press.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 160

Mirjam Sprong | Adolescents at risk of psychosis

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 161

Mirjam Sprong | Adolescents at risk of psychosis

Chapter 6

Summary and general discussion

Mirjam Sprong

Rudolf Magnus Institute of Neuroscience/Department of Child and Adolescent Psychiatry, University Medical Center Utrecht, the Netherlands

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 162

Mirjam Sprong | Adolescents at risk of psychosis

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 163

Mirjam Sprong | Adolescents at risk of psychosis

1. Summary of the aims Psychotic episodes do no exclusively occur in the context of psychotic disorders, but can occur in individuals with a wide range of characteristics and disorders. Comparing vulnerability markers for psychosis in different high-risk populations is important, because it will ultimately lead to more insight into the many different biological and environmental causes of the psychotic syndrome. This dissertation concentrates on the comparison of two groups of adolescents that are presumably at high risk for developing a first psychotic episode. The first group consists of help-seeking adolescents presenting with prodromal-like symptoms that meet the research criteria for ARMS. The second group consists of adolescents diagnosed with the PDD-NOS subtype MCDD. The main aims of this dissertation are: (1) to cross-sectionally compare potential neurocognitive and behavioral vulnerability markers for psychosis in these two high-risk groups, and (2) to explore social cognitive impairments as potential vulnerability markers for psychosis.

2. Summary of the results In Chapter 2 we showed that the two high-risk groups could be distinguished by their early-childhood behavior and autism traits. However, when they were assessed in adolescence, they did not differ with regard to schizotypal personality traits and basic symptoms, as well as disorganized and general high-risk symptoms. Moreover, the vast majority (78%) of adolescents with MCDD met the research criteria for ARMS, which suggests that they may be in the prodromal phase of a psychotic episode. As a group, the ARMS adolescents showed higher levels of positive and negative high-risk symptoms than the MCDD adolescents. Therefore, based on the assumption that the nonspecific basic symptoms generally develop first, followed by positive, and later negative symptoms (Gross 1997), the ARMS group appears to be at more imminent risk of developing a psychotic episode. We discussed that this might be explained by the fact that the ARMS group was older. In Chapter 3 we focused on some of the behavioral and neurocognitive impairments that have frequently been identified as vulnerability markers for schizophrenia. While adolescents in both high-risk groups experienced significant difficulties in their schoolwork and interactions with friends and families, they showed impairment on only a few, but normal functioning on most of the assessed neurocognitive domains. Both high-risk groups had a poorer performance on tasks assessing attention/working memory and verbal output generation, but the differences with the NPC group were only small. Psychomotor speed was also reduced in both high-risk groups, with a small

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 164

Mirjam Sprong | Adolescents at risk of psychosis effect size in the ARMS group, and a medium effect size in the MCDD group. Social cognition is defined as the mental operations underlying social interactions. Because social impairments have frequently identified in the premorbid phase of psychotic disorders, we hypothesized that social cognitive impairments would also be present before psychosis-onset, and represent a vulnerability marker for psychosis. In Chapter 4 the two high-risk groups are compared on one measure of social cognition, i.e. facial affect processing. Neither of the two high-risk groups had overall impairments in the accuracy of recognizing facial expressions. However, the MCDD group showed specific deficits in the accuracy of recognizing fear, and an overall reduced speed of processing complex visual information (i.e. visuospatial patterns, facial identity, and facial expressions), with small to medium effect sizes. Reported studies in individuals with PDD suggest that these impairments may be associated with the PDD spectrum, rather than only with the MCDD subtype of PDD-NOS. At this point it is worth noting that processing speed and psychomotor speed reflect two different neurocognitive domains (Morrens et al. 2007). Processing speed measured using a reaction time paradigm involves the rapid initiation of responses that are elicited by external cues. These reaction times are sensitive to deficits in higher level neurocognitive domains such as vigilance and speed of information processing. In contrast, psychomotor speed as measured with the Finger Tapping Test (Rombouts 2002) does not address higher order neurocognitive processes1. Chapter 5 describes the results of our meta-analysis of reports on the association between schizophrenia and another measure of social cognition, i.e. mentalizing or Theory of Mind. This is the cognitive ability to attribute mental states such as thoughts, beliefs and intentions to people, allowing an individual to explain, manipulate and predict behavior. The results of our meta-analysis indicate that there is a statistically significant and stable mentalizing impairment in individuals diagnosed with schizophrenia. The estimated overall effect size is large, and not significantly affected by study characteristics. The finding that remitted schizophrenia patients also show impairment of mentalizing suggests that this may represent a trait marker for schizophrenia, and may thus be present even before the onset of a first psychotic episode. This is further corroborated by evidence from the literature that mentalizing is also impaired in individuals at genetic risk for schizophrenia, and that mentalizing impairment is positively associated with schizotypal traits. In conclusion, both high-risk groups report a broad range of high-risk traits and symptoms, as well as problems with their schoolwork and interactions with friends and family. However, despite these behavioral problems they show a relatively intact functioning on most of the assessed neurocognitive domains, although their psychomotor speed, attention/working memory, and verbal output generation are somewhat poorer compared to NPCs. Dysfunctions of these neurocognitive domains 1

In fact, in our MCDD sample the number of preference hand finger tappings was not significantly related to any of the reaction time measures (all bivariate correlations Pearson’s r < -.20, all p-values > .35).

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 165

Mirjam Sprong | Adolescents at risk of psychosis thus represent potential vulnerability markers for psychosis. Our findings further indicate that of the social cognitive domains, mentalizing impairment but not facial affect recognition may represent a vulnerability marker for psychosis.

3. Comparison with other ARMS studies and methodological issues The general lack of major neurocognitive impairments in the two high-risk groups is in contrast with our a priori hypotheses. These were for a large part based on studies in individuals with an ARMS. In this section some possible explanations for our negative findings are discussed, as well as some methodological limitations of this study. In our opinion, the most important factor distinguishing the current study from most other ARMS studies is the younger age of the participants. Young adolescents are further away from the usual age of onset of first schizophrenia-related psychoses, and thus may show less of a premorbid neurocognitive decline, and - because treatment has started relatively early - a lower rate of transition to psychosis. It has also been suggested that while subclinical psychotic symptoms are more stable or “true” risk indicators in older adolescents and adults, they may be more transitory phenomena in young adolescents (Olsen and Rosenbaum 2006a). This would also entail a lower transition rate in younger ARMS participants. A lower transition rate means a higher rate of false positives (i.e. adolescents who meet the research criteria for high risk but never develop a psychotic episode). These false positives may have reduced the group differences in neurocognitive functioning between the ARMS group and the NPC group. A second issue related to the age of the participants is whether the psychometric properties of the selection instruments (i.e. the SIPS and BSABS-P interviews) are the same for young adolescents as for individuals in the age range in which these instruments are normally used (i.e. ≥ 16 years). Because the interviews are semistructured, there was some freedom to modify questions according to the comprehension level of the participants, but the questions remain whether all items were properly understood, and whether they had the same meaning in all participants. In addition, the researchers may inadvertently have rated symptoms differently in younger participants than in older participants. These age-related factors may have contributed to the differences between our ARMS sample and the samples of other ARMS studies. Third, differences in study designs may also affect the homogeneity of samples across ARMS studies (Olsen and Rosenbaum 2006a). For example, individuals referred from clinical settings are likely to have more psychopathology than individuals referred from the work place or school. Van Os and Delespaul (2005) have argued that “it is the clinical context of the psychotic experience that determines the risk for transition to schizophrenia”. The ARMS adolescents recruited at the UMC were all help-seeking and

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 166

Mirjam Sprong | Adolescents at risk of psychosis met the research criteria for ARMS. However, many of them had not sought help for their subclinical psychotic symptoms, but for other mental health problems such as affective disorder, attention-deficit/hyperactivity disorder, parent-child relational problems or other social problems. Therefore, in a vigorous attempt to include as many ARMS adolescents as possible, we may have included more false-positives than if we would have only included help-seeking adolescents meeting the ARMS criteria, who had been filtered out by mental-health care professionals as “at-risk for psychosis”. Again, the higher rate of false-positives may have reduced the group differences in neurocognitive functioning between the ARMS group and the NPC group. Fourth, there are other sources of heterogeneity of samples across ARMS studies (Olsen and Rosenbaum 2006a and 2006b). These include differences in selection instruments (e.g. the SIPS versus the Comprehensive Assessment of At-Risk Mental States), differences in the criteria for stability and duration of prodromal symptoms, differences in thresholds for psychosis (i.e. psychotic symptoms with a duration of more than one week versus more than one month), and the use of additional inclusion criteria such as the presence of basic symptoms (e.g. this dissertation) or negative symptoms. Unfortunately, it is unclear to what extent those sources of heterogeneity can explain the unexpected results of the present study. Fifth, the hypothesis that the adolescents with MCDD would show impairments on the assessed neurocognitive domains was based on the assumption that they represent a group with an elevated risk for psychosis. This assumption is corroborated by only one follow-up study (Van Engeland and Van der Gaag 1994). Follow-up of the adolescents with MCDD into adulthood is necessary to establish whether they can truly be considered to be at high risk for psychosis. Sixth, because DUPS is a naturalistic, follow-along study, medication use was not an exclusion criterion for the high-risk groups. Clinical trials investigating the possibility of delaying or preventing psychosis by psychopharmacological intervention in individuals with an ARMS have often been strongly criticized because of the negative side effects of anti-psychotics, such as excessive weight gain, and the lack of knowledge of the longterm effects of antipsychotic medication on the developing adolescent brain (e.g. Cornblatt et al. 2001). We were therefore surprised at the high rates of high-risk patients that were prescribed antipsychotic medication in the absence of overt psychosis (i.e. 25% in the ARMS group and 50% in the MCDD group), an experience that is shared by some other researchers (Phillips et al. 2005). There is preliminary evidence that pharmacotherapy, but also psychological and psychosocial interventions, may delay, if not prevent, the onset of a psychotic disorder in ARMS individuals (McGlashan et al. 2006; McGorry et al. 2002; Morrison et al. 2004). The fact that medication use was not an exclusion criterion for the high-risk groups may thus ultimately affect transition rates. Moreover, medication use may have also affected symptomatology and neurocognitive

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 167

Mirjam Sprong | Adolescents at risk of psychosis functioning in the high-risk groups. And finally, some methodological limitations may have also affected the results of this study. First, the groups were not gender-matched, which was as expected because PDDs are more prevalent in males than in females (Volkmar et al. 2004). Second, the groups were not matched in age, which is also not surprising because adolescents with MCDD by definition have early-onset developmental abnormalities, and thus in almost every case had come to the attention of mental health care professionals at an early age. We statistically adjusted neurocognitive performance for gender and age, but it would have been preferable to have had groups that were matched. Third, both high-risk groups showed lower levels of (verbal) intellectual functioning (IQ) than the NPC group, although they did score around the level of the standardized mean (= 100). After careful deliberation, we decided not to statistically adjust neurocognitive performance for group differences in IQ, because an IQ-score reflects an individual’s performance on a combination of neurocognitive tasks, including tasks that assess, or are influenced by the neurocognitive domains of interest. Adjusting for group differences in IQ would therefore also reduce the group differences on the dependent variables. Moreover, we were not interested in whether there were specific impairments on the dependent variables apart from impairments in general intellectual functioning. Although not correcting for IQ is a matter of debate, the fact remains that even despite having lower IQ-scores, both high-risk groups were relatively unimpaired on most of neurocognitive domains. Apart from the abovementioned methodological limitations, the most important limitation of this dissertation is the fact that only cross-sectional data are presented. Follow-up of the participants into adulthood is necessary to determine who will make a transition to psychosis, and thus establish whether the “high-risk” adolescents can truly be considered to be “at high risk” for developing a psychotic episode. Moreover, followup data will allow for analyzing the predictive validity of the high-risk traits and symptoms, and of the impairments in psychomotor speed, attention/working memory, and verbal output generation. The fact that we did not observe major neurocognitive impairments in our high-risk groups does not exclude the possibility that they may still be vulnerability markers for psychosis. Some premorbid neurocognitive impairments may not emerge until closer to the onset of psychosis, or perhaps the rates of falsepositives were too high to discriminate between the high-risk groups and the NPC group. Data on the follow-up assessments will be part of a second dissertation, which is planned to be published within the next two years. In summary, it is unclear why the two high-risk groups did not show the expected deficits on most of the assessed neurocognitive domains. Possible explanations include the younger age of our ARMS sample compared to the samples in most other ARMS studies, high rates of false positives and high rates of medication use in both high-risk

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 168

Mirjam Sprong | Adolescents at risk of psychosis groups, and methodological limitations such as the fact that the groups were not matched on demographic variables.

4. Validity of the distinction between the two high-risk groups An important question raised by the studies in this dissertation is, whether the two highrisk groups can truly be differentiated. After all, they did not differ regarding most of the high-risk traits and symptoms, and they reported similar levels of social impairment. Moreover, the majority of adolescents with MCDD met the research criteria for ARMS. In chapter 2 we argued that the MCDD group was much more impaired in early childhood than the ARMS group, and that the groups could be differentiated by the fact that the adolescents with an ARMS by definition did not have an MCDD diagnosis. However, a quarter of the adolescents with an ARMS had had a mental health contact before the age of twelve, which implies that they had had childhood-onset behavioral problems2. Retrospective studies in individuals with schizophrenia have elicited associations between poor premorbid adjustment and male sex, an earlier age at first-psychosis onset, increased severity of illness, more negative symptoms, and a poorer outcome (reviewed by Schmael et al. 2007). It would therefore have been interesting to divide our ARMS sample in a subgroup with early childhood-onset behavioral problems and a subgroup with a normal early development. One could for instance expect that the “early-onset” subgroup would be younger, have a higher rate of males, and more autism traits than the second subgroup. Unfortunately, because the mental health care history of most adolescents with an ARMS started after age twelve, only crude and retrospectively collected data on early childhood development were available for most of them (i.e. age of first contact mental health care and/or type of primary education). In contrast, because most adolescents with MCDD had come into contact with mental health care from a very early age, information on their early childhood years was in many cases well-documented in their medical files. Using these crude data, the “early-onset” ARMS group was too small to be analyzed separately.

5. Recommendations for future research The necessity of long-term follow-up of the high-risk adolescents beyond the age window in which first psychotic episodes commonly emerge has already been mentioned. However, to calculate the sensitivity and specificity of the ARMS criteria for the transition to psychosis it is also important to follow-up on the screen-negatives, i.e. those adolescents that were referred to the study because of a suspicion of high-risk for psychosis that agreed to participate, but did not meet the research criteria for ARMS as 2

In fact, 4 of the 49 (8%) ARMS adolescents of the UMC site had been diagnosed with a PDD at least once in their lives (2 Asperger’s syndrome, and 2 PDD-NOS)

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 169

Mirjam Sprong | Adolescents at risk of psychosis assessed with the SIPS and BSABS-P interviews. Thus far, data on these screen negatives have never been reported. Although ethically more complicated, we also recommend following-up on the referred adolescents that refused participation, and the adolescents who were not invited for participation because it was judged that the assessments would be too burdensome for them. It is reasonable to assume that these individuals may have more severe psychopathology than those that did participate. Future research should address the psychometric properties including the predictive validity of the screening interviews. Thus far mainly preliminary data have been published. Also, the use of the combination of these and other (yet to be developed) screening instruments, including instruments that assess attenuated negative symptoms should be investigated, because it may lead to a more accurate identification of individuals at imminent risk for developing psychosis (Olsen and Rosenbaum 2006b). An important question raised by this dissertation is whether the instruments have the same psychometric properties in different populations, for example young adolescents vs adults, and ARMS vs MCDD. Finally, to unravel the many different biological and environmental causes of psychosis, future studies should focus on various other high-risk populations, including individuals with a genetic risk for schizophrenia, Klinefelter syndrome, and 22q11-deletion syndrome, and compare those high-risk groups on potential neurocognitive and behavioral vulnerability markers for psychosis. In addition, one should investigate other potential vulnerability markers in these populations, including biological markers such as genetics and abnormalities of brain structures and functioning.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 170

Mirjam Sprong | Adolescents at risk of psychosis

References Cornblatt,B.A., Lencz,T., and Kane,J.M., 2001. Treatment of the schizophrenia prodrome: is it presently ethical? Schizophrenia Research 51, 31-38. Gross,G., 1997. The onset of schizophrenia. Schizophrenia Research 28, 187-198. McGlashan,T.H., Zipursky,R.B., Perkins,D., Addington,J., Miller,T., Woods,S.W., Hawkins,K.A., Hoffman,R.E., Preda,A., Epstein,I., Addington,D., Lindborg,S., Trzaskoma,Q., Tohen,M., and Breier,A., 2006. Randomized, double-blind trial of Olanzapine versus placebo in patients prodromally symptomatic for psychosis. The American Journal of Psychiatry 163, 790-799. McGorry,P.D., Yung,A.R., Phillips,L.J., Yuen,H.P., Francey,S., Cosgrave,E.M., Germano,D., Bravin,J., McDonald,T., Blair,A., Adlard,S., and Jackson,H., 2002. Randomized controlled trial of interventions designed to reduce the risk of progression to first-episode psychosis in a clinical sample with subthreshold symptoms. Archives of General Psychiatry 59, 921-928. Morrens,M., Hulstijn,W., and Sabbe,B., 2007. Psychomotor slowing in schizophrenia. Schizophrenia Bulletin 33, 1038-1053. Morrison,A.P., French,P., Walford,L., Lewis,S.W., Kilcommons,A., Green,J., Parker,S., and Bentall,R.P., 2004. Cognitive therapy for the prevention of psychosis in people at ultra-high risk: randomised controlled trial. The British Journal of Psychiatry 185, 291-297. Olsen,K.A. and Rosenbaum,B., 2006a. Prospective investigations of the prodromal state of schizophrenia: review of studies. Acta Psychiatrica Scandinavica 113, 247-272. Olsen,K.A. and Rosenbaum,B., 2006b. Prospective investigations of the prodromal state of schizophrenia: assessment instruments. Acta Psychiatrica Scandinavica 113, 273-282. Phillips,L.J., McGorry,P.D., Yung,A.R., McGlashan,T.H., Cornblatt,B., and Klosterkötter,J., 2005. Prepsychotic phase of schizophrenia and related disorders: recent progress and future opportunities. The British Journal of Psychiatry Supplement 48, s33-s44. Rombouts, R.P., 2002a. Finger Tapping Test, CDLJava [Computer software]. Lelystad: BuroTesteR. Schmael,C., Georgi,A., Krumm,B., Buerger,C., Deschner,M., Nothen,M.M., Schulze,T.G., and Rietschel,M., 2007. Premorbid adjustment in schizophrenia - an important aspect of phenotype definition. Schizophrenia Research 92, 50-62. Van Engeland,H. and Van der Gaag,R.J., 1994. MCDD in childhood: a precursor of schizophrenic spectrum disorders. Schizophrenia Research 11, 197.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 171

Mirjam Sprong | Adolescents at risk of psychosis Van Os,J. and Delespaul,P., 2005. Toward a world consensus on prevention of schizophrenia. Dialogues in clinical neuroscience 7, 53-67. Volkmar,F.R., Lord,C., Bailey,A., Schultz,R.T., and Klin,A., 2004. Autism and pervasive developmental disorders. Journal of Child Psychology and Psychiatry, and Allied Disciplines 45, 135-170.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 172

Mirjam Sprong | Adolescents at risk of psychosis

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 173

Mirjam Sprong | Adolescents at risk of psychosis

Appendix

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 174

Mirjam Sprong | Adolescents at risk of psychosis

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 175

Mirjam Sprong | Adolescents at risk of psychosis

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 176

Mirjam Sprong | Adolescents at risk of psychosis

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 177

Mirjam Sprong | Adolescents at risk of psychosis

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 178

Mirjam Sprong | Adolescents at risk of psychosis

References Andreasen,N.C., Flaum,M., and Arndt,S., 1992. The Comprehensive Assessment of Symptoms and History (CASH): an instrument for assessing diagnosis and psychopathology. Archives of General Psychiatry 49, 615-623. Arrindell,W.A., De Groot,P.M., and Walburg,J.A., 1980. Schaal voor Interpersoonlijk Gedrag (SIG). Lisse: Swets Test Publishers, Swets en Zeitlinger b.v. Beck,A.T., Ward,C.H., Mendelson,M., Mock,J.E., and Erbaugh,J.K., 1961. An inventory for measuring depression. Archives of General Psychiatry 4, 561-571. Berument,S.K., Rutter,M., Lord,C., Pickles,A., and Bailey,A., 1999. Autism screening questionnaire: diagnostic validity. The British Journal of Psychiatry 175, 444-451. Cannon-Spoor,H.E., Potkin,S.G., and Wyatt,R.J., 1982. Measurement of premorbid adjustment in chronic schizophrenia. Schizophrenia Bulletin 8, 470-484. Cohen,D.J., Towbin,K.E., Mayes,L., and Volkmar,F., 1994. Developmental psychopathology of Multiplex Developmental Disorder. In: S.L.Friedman and H.C.Haywood (Series Eds.), Developmental follow-up: concepts, genres, domains, and methods. New York: Academic Press, Inc., pp. 155-179. Cole,J.D. and Kazarian,S.S., 1988. The Level of Expressed Emotion Scale: a new measure of expressed emotion. Journal of Clinical Psychology 44, 392-397. Cornblatt,B.A., 2000. Continuous Performance Test - Identical Pairs version, release 2.0 [Computer software and manual], New York: Author. De Sonneville,L.M.J., 2003. Amsterdam Neuropsychological Tasks (ANT) [Computer software and manual]. Amstelveen: SONAR. John,R.S., Mednick,S.A., and Schulsinger,F., 1982. Teacher reports as a predictor of a schizophrenia and borderline schizophrenia: a Bayesian decision analysis. Journal of Abnormal Psychology 91, 399-413. Klin,A., 2000. Attributing social meaning to ambiguous visual stimuli in higher-functioning autism and Asperger syndrome: The Social Attribution Task. Journal of Child Psychology and Psychiatry 41, 831-846.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 179

Mirjam Sprong | Adolescents at risk of psychosis Klosterkötter,J., Ruhrmann,S., Schultze-Lutter,F., Salokangas,R.K., Linszen,D., Birchwood,M., Juckel,G., Morrison,A., Vazquez-Barquero,J.L., Hambrecht,M., and Von Reventlow,H., 2005. The European Prediction of Psychosis Study (EPOS): integrating early recognition and intervention in Europe. World Psychiatry 4, 161-167. Landgraf,J.M., Abetz,L., and Ware,J.E., 1999. Child Health Questionnaire (CHQ): a user's manual. Boston: HealthAct. Langdon,R. and Coltheart,M., 1999. Mentalising, schizotypy, and schizophrenia. Cognition 71, 43-71. Langdon,R. and Coltheart,M., 2004. Recognition of metaphor and irony in young adults: the impact of schizotypal personality traits. Psychiatry Research 125, 9-20. Langdon,R., Coltheart,M., and Ward,P.B., 2006. Empathetic perspective-taking is impaired in schizophrenia: evidence from a study of emotion attribution and theory of mind. Cognitive Neuropsychiatry 11, 133-155. Langdon,R., Coltheart,M., Ward,P.B., and Catts,S.V., 2002. Disturbed communication in schizophrenia: the role of poor pragmatics and poor mind-reading. Psychological Medicine 32, 1273-1284. Lord,C., Rutter,M., and Le Couteur,A., 1994. Autism Diagnostic Interview-Revised (ADI-R): a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. Journal of Autism and Developmental Disorders 24, 659-685. Luteijn,F., Starren,J., and Van Dijk,H., 2000. Handleiding Nederlandse Persoonlijkheids Vragenlijst (NPV) herziene uitgave. Lisse: Swets Test Publishers, Swets en Zeitlinger b.v. Luteijn,F., Van Dijk,H., and Van der Ploeg,F.A.E., 1989. Handleiding Junior Nederlandse Persoonlijkheidsvragenlijst (NPV-J) - herziene uitgave. Lisse: Swets en Zeitlinger b.v. Maxwell,M.E., 1992. Family Interview for Genetic Studies (FIGS): a manual for FIGS. Bethesda: Clinical Neurogenetics Branch, Intramural Research Program, National Institute of Mental Health. McGlashan, T. H., Miller, T. J, and Woods, S. W. Structured Interview for Prodromal Syndromes (SIPS) version 3.0. 2001. New Haven: PRIME Research Clinic, Yale School of Medicine. Patterson,P., Skeate,A., and Birchwood,M., 2002. Trauma and Distress Scale (TADS-EPOS 1.2). Birmingham: University of Birmingham. Raat,H., Landgraf,J.M., Bonsel,G.J., Gemke,R.J., and Essink-Bot,M.L., 2002. Reliability and validity of the child health questionnaire-child form (CHQ-CF87) in a Dutch adolescent population. Quality of Life Research 11, 575-581.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 180

Mirjam Sprong | Adolescents at risk of psychosis Raine,A., 1991. The SPQ: a scale for the assessment of schizotypal personality based on DSM-III-R criteria. Schizophrenia Bulletin 17, 555-564. Rey, A. (1964). L' examen clinique en psychologie. Paris: Presses Universitaires de France. Rombouts, R.P., 2002a. Finger Tapping Test, CDLJava [Computer software]. Lelystad: BuroTesteR. Rombouts, R.P., 2002b. Spatial Working Memory Test, CDLJava [Computer software]. Lelystad: BuroTesteR. Rombouts, R.P., 2002c. Card Sorting Test, CDLJava [Computer software]. Lelystad: BuroTesteR. Saan,R.J., Deelman,B.G., 1986. De 15 Woordentaak A en B [15 Words task]. Groningen: Department of Neuropsychology, Academic Hospital Groningen. Schultze-Lutter,F. and Klosterkötter,J., 2002. Bonn Scale for the Assessment of Basic Symptoms Prediction list (BSABS-P). Cologne: University of Cologne. Sheehan,D.V., Lecrubier,Y., Sheehan,K.H., Amorim,P., Janavs,J., Weiller,E., Hergueta,T., Baker,R., and Dunbar,G.C., 1998. The Mini - International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. Journal of Clinical Psychiatry 59, Supplement 20, 22-33. Smith,M. and Epping-Jordan,J., 2000. World Health Organization - Disability Assessment Schedule (WHODAS-II), training manual: a guide to administration. Geneva: World Health Organization. Ter Smitten,M.H., Smeets,R.M.W., and Van den Brink,W., 1997. Composite International Diagnostic Interview (CIDI) - Life Time, basic version 2.1. Geneva: World Health Organization. Van Mastrigt,S. and Addington,J., 2002. Assessment of premorbid function in first-episode schizophrenia: modifications to the Premorbid Adjustment Scale. Journal of Psychiatry and Neuroscience 27, 92-101. Vollema,M.G. and Hoijtink,H., 2000. The multidimensionality of self-report schizotypy in a psychiatric population: an analysis using multidimensional Rasch models. Schizophrenia Bulletin 26, 565-575. Warreyn, P. and Roeyers, H., 2001. Dutch translation of the Social Communication Questionnaire by Rutter et al. (prepublication material). Los Angeles: Western Psychological Services. Wechsler Adult Intelligence Scale - III NL, 1997. Harcourt Publishers, The Psychological Corporation. Wechsler Intelligence Scale for Children - III NL, 2002. London: Harcourt Assessment, The Psychological Corporation.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 181

Mirjam Sprong | Adolescents at risk of psychosis

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 182

Mirjam Sprong | Adolescents at risk of psychosis

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 183

Mirjam Sprong | Adolescents at risk of psychosis

Nederlandse samenvatting

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 184

Mirjam Sprong | Adolescents at risk of psychosis

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 185

Mirjam Sprong | Adolescents at risk of psychosis

1. Inleiding Een psychose is een ernstige verstoring van de realiteitstoetsing, hetgeen zich kan uiten in een gebrek aan inzicht in het feit dat de vreemde ideeën (wanen) of percepties (hallucinaties) die men ervaart niet berusten op de werkelijkheid, of in een ongewone manier van denken en doen (desorganisatie). Psychoses maken deel uit van de diagnostische criteria voor psychotische stoornissen, waaronder bijvoorbeeld schizofrenie en schizoaffectieve stoornis worden geschaard. Psychoses kunnen echter ook bij andere psychiatrische stoornissen voorkomen, in het bijzonder bij affectieve stoornissen. Schizofrenie is de meest voorkomende en meest bestudeerde psychotische stoornis. Ongeveer 1% van de bevolking lijdt aan schizofrenie en het aantal nieuwe gevallen per jaar ligt tussen de 0.025 en 0.05%. De diagnose wordt vaker gesteld in mannen dan in vrouwen. De aandoening komt meestal in de late adolescentie of jong-volwassenheid voor het eerst tot uiting. Schizofrenie wordt over het algemeen beschouwd als een heterogene stoornis met betrekking tot de klinische kenmerken en oorzaken. Sommige onderzoekers pleiten er daarom voor om het concept schizofrenie af te schaffen en zich in het wetenschappelijke onderzoek te richten op specifieke symptomen van schizofrenie, zoals psychoses. Ook in deze dissertatie zijn we niet zozeer geïnteresseerd in de ontwikkeling van psychotische stoornissen, als wel in de ontwikkeling van psychotische episodes. Deze worden binnen dit onderzoek gedefinieerd als het hebben van psychotische symptomen (i.e. wanen, hallucinaties en/of desorganisatie van denken en gedrag) die het functioneren ernstig verstoren en langer dan een week aanhouden (zie Hoofdstuk 1). Veel retrospectieve, maar ook enkele prospectieve studies hebben aangetoond, dat sommige mensen met de diagnose schizofrenie al lang voor de eerste psychotische episode zijn te onderscheiden van mensen zonder de diagnose, bijvoorbeeld met betrekking tot het later behalen van vroege ontwikkelingsmijlpalen, beperkingen in het neurocognitief functioneren (m.n. intelligentie en aandachtsproblemen), lagere schoolprestaties en sociaal dysfunctioneren. Dit duidt erop dat de pathologische processen die kwetsbaar maken voor de ziekte al vroeg in de vroege kindertijd aanwezig kunnen zijn. Verschillende onderzoekers wijzen op het mogelijke belang van de verschillen tussen personen met schizofrenie die al vanaf de vroege kindertijd een abnormale ontwikkeling lieten zien en degenen die zich gedurende de gehele kindertijd relatief normaal ontwikkelden, waarna er veranderingen in de persoonlijkheid en het gedrag in de adolescentie of vroege volwassenheid optraden. Zo lijkt in de eerste groep vaker sprake te zijn van een hoog percentage mannen, structurele hersenafwijkingen,

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 186

Mirjam Sprong | Adolescents at risk of psychosis neurocognitieve problemen, een vroeg begin van de aandoening en een slechtere prognose. Psychoses komen overigens niet alleen voor in het kader van psychotische en affectieve stoornissen. Andere stoornissen die worden geassocieerd met een verhoogd risico op psychotische symptomen zijn bijvoorbeeld de pervasieve ontwikkelingsstoornissen, het Klinefelter syndroom, het 22q11-deletie syndroom en sommige DSM-IV persoonlijkheidsstoornissen, in het bijzonder die uit cluster A. Er zijn dus verschillende ontwikkelingstrajecten naar psychose, waarbij mogelijk verschillende oorzaken een rol spelen. Kwetsbaarheidsmodellen stellen dat predispositionele factoren in combinatie met externe stressoren de kans op de ontwikkeling van een aandoening vergroten, terwijl interne en externe protectieve factoren deze kans verkleinen. Daarbij noemen we predispositionele factoren die waarneembaar zijn in de premorbide fase kwetsbaarheidindicatoren. Meer kennis van de kwetsbaarheidindicatoren voor psychoses vergroot het inzicht in de mogelijke oorzaken ervan. Daarnaast kan men die kennis gebruiken om te bepalen welke personen een verhoogd risico hebben op het ontwikkelen van psychoses, alsook om vroege interventiestrategieen te ontwikkelen. Kwetsbaarheidindicatoren voor psychose worden vrijwel altijd bestudeerd in het kader van schizofrenie. Echter, het vergelijken van kwetsbaarheidsindicatoren in (hoog-risico) populaties met verschillende ontwikkelingstrajecten naar psychose is van belang, omdat daarmee meer inzicht kan worden verworven in de verschillende oorzaken van psychoses.

2. Doelen In het kader van deze dissertatie werden potentiële kwetsbaarheidsindicatoren voor psychose onderzocht in twee groepen 12-18 jarige adolescenten, van wie wordt gedacht dat zij een verhoogd risico hebben op het ontwikkelen van een eerste psychose.

2.1. At Risk Mental State De eerste hoog-risico groep bestond uit adolescenten die zich hebben aangemeld bij instellingen voor geestelijke gezondheidszorg en die symptomen hebben die erop wijzen dat zij zich mogelijk in een prodromale fase van een psychotische episode bevinden. Dit is de premorbide fase die begint op het moment dat iemands ervaringen en gedrag gaan afwijken van wat hij/zij of de naaste omgeving daarvoor gewend was en eindigt op het moment dat de psychotische episode begint. De prodromale fase wordt onder meer gekenmerkt door een geleidelijke achteruitgang in het normale functioneren op school of werk, verminderde interesses, verminderde behoefte aan sociale contacten, sociale angst, een depressieve stemming, slaapproblemen, ongewone gedragingen,

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 187

Mirjam Sprong | Adolescents at risk of psychosis subtiele veranderingen in denken, emoties en waarnemingen, en subklinische psychotische symptomen zoals hallucinaties en waanideeen. De meeste personen met schizofrenie, maar ook mensen met andere psychotische stoornissen ervaren zo een prodromale fase. De laatste 10 jaar wordt veel onderzoek gedaan bij mensen die symptomen hebben die worden geassocieerd met de prodromale fase van psychotische stoornissen. Het doel van deze studies is onder meer het starten van behandeling voorafgaand aan de eerste psychotische episode om zo het ontstaan ervan uit te stellen of zelfs te voorkomen. De meeste studies richten zich op personen die hulp hebben gezocht voor mentale problemen en die voldoen aan een of meer van de volgende symptoomcategorieen: (1) subklinische positive symptomen, (2) een kortdurende (i.e. korter dan een week) psychotische episode die vanzelf voorbij gaat, en (3) een combinatie van een genetisch risico op een psychotische stoornis en een aanzienlijke achteruitgang in het functioneren in het afgelopen jaar. Enkele studies, inclusief de huidige studie, selecteren (daarnaast) op basis van de aanwezigheid van “basis symptomen”. Dat zijn stoornissen in het denken, de waarneming en het motorisch functioneren, die vaak alleen door de persoon zelf ervaren worden. Omdat niet iedereen met bovengenoemde kenmerken ook daadwerkelijk een psychose zal ontwikkelen, wordt in deze context niet gesproken van prodromale symptomen, maar van bijvoorbeeld “mogelijk-prodromale”, “ultra-hoog risico” of “klinisch hoog-risico” symptomen, of van een “at risk mental state” (ARMS). De eerste publicaties van ARMS studies lieten hoge percentages transitie naar psychose zien van 28-46% binnen zes maanden en 35-54% binnen een jaar. In de recentere studies liggen de transitiepercentages veelal lager, bijvoorbeeld 10% binnen zes maanden en 15% binnen een jaar.

2.2. Multiple Complex Developmental Disorder De tweede hoog-risico groep die werd onderzocht in het kader van deze dissertatie bestond uit adolescenten met Multiple Complex Developmental Disorder (MCDD). MCDD wordt beschouwd als een subtype van de Pervasieve Ontwikkelingsstoornissen Niet Anderszins Omschreven (PDD-NOS), die (nog) niet is opgenomen in de classificatiesystemen voor psychiatrische aandoeningen. PDD-NOS ligt op het continuum van de Pervasieve Ontwikkelingsstoornissen, waaronder ook Autistische stoornis, Stoornis van Rett, Desintegratiestoornis van de kinderleeftijd en Stoornis van Asperger worden geschaard. Kinderen met PDD-NOS hebben autistische symptomen die varieren in ernst, namelijk:

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 188

Mirjam Sprong | Adolescents at risk of psychosis (1) tekortkomingen in de sociale interactie en communicatie, (2) tekortkomingen in de ontwikkeling van gevarieerd spel, en (3) rigide of stereotype gedragspatronen en interesses. Ze voldoen echter niet aan alle diagnostische criteria voor een autistische stoornis. Cohen et al. onderscheidden binnen deze heterogene groep kinderen met PDD-NOS, een groep kinderen met: (1) affectregulatiestoornissen (angsten en agressie), (2) stoornissen in de gevoeligheid voor sociale signalen en stoornissen in de ontwikkeling van wederkerige relaties, en (3) stoornissen in het denken (bijvoorbeeld onnavolgbaar van de hak op de tak springen, bizarre fantasieen, moeite hebben met het onderscheid tussen fantasie en werkelijkheid). Deze verschijnselen treden op vanaf de vroege kinderleeftijd, meestal vanaf drie jaar. Cohen et al. introduceerden de term MCDD en ontwikkelden diagnostische criteria voor dit syndroom (Hoofdstuk 1). Een follow-up studie (n = 55) liet zien dat kinderen met MCDD een verhoogd risico hebben op het ontwikkelen van psychotische episodes: 22% van de kinderen die werden gevolgd tot in de adolescentie en 64% van de kinderen die werden gevolgd tot op jong-volwassen leefheid ontwikkelden een schizofrenie-spectrum stoornis.

2.3. Doelen De doelen van deze dissertatie waren: (1) een cross-sectionele vergelijking te maken van potentiële neurocognitieve en gedragsmatige kwetsbaarheidindicatoren voor psychose in de twee bovengenoemde hoog-risicogroepen, en (2) het exploreren van sociaal-cognitieve beperkingen als potentiële kwetsbaarheidindicatoren voor psychose. De opzet van het onderzoek en de inclusie en exclusiecriteria voor de hoogrisicogroepen en voor een gezonde controle groep worden uitgebreid beschreven in Hoofdstuk 1.

3. Resultaten De eerste stap was het vergelijken van hoog-risico (i.e. mogelijk-prodromale) symptomen en schizotypische persoonlijkheidstrekken in de twee hoog-risicogroepen. Omdat de ARMS groep per definitie mogelijk-prodromale symptomen heeft en de MCDD groep niet, verwachtten wij dat de eerstgenoemde meer van deze symptomen zou hebben dan de laatstgenoemde. Omdat van beide groepen werd verondersteld dat zij een verhoogd risico hebben op het ontwikkelen van een psychose en omdat

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 189

Mirjam Sprong | Adolescents at risk of psychosis schizotypische persoonlijkheidstrekken een maat zijn voor psychose-gevoeligheid, verwachtten we dat beide groepen meer van deze trekken zouden hebben dan de gezonde controle groep. In Hoofdstuk 2 wordt beschreven dat de twee hoog-risico groepen zoals te verwachten verschilden in het aantal autistische trekken dat door ouders werd gerapporteerd. Daarnaast had de MCDD groep in vergelijking met de ARMS groep vaker ontwikkelingsproblemen in de vroege kindertijd, hetgeen tot uiting kwam in een eerste contact met de geestelijke gezondheidszorg voor de leeftijd van zes jaar. Ook hadden de meeste jongeren met MCDD als kind Speciaal Basisonderwijs gevolgd. De twee hoog-risico groepen verschilden echter niet van elkaar met betrekking tot schizotypische persoonlijkheidstrekken en basis symptomen, alsook met betrekking tot desorganisatie en algemene hoog-risico symptomen. Het meerendeel van de jongeren met MCDD (78%) voldeed bovendien aan de onderzoekscriteria voor ARMS, hetgeen suggereert dat zij zich mogelijk in een prodromale fase van een psychotische episode bevinden. Als groep rapporteerden de adolescenten met een ARMS echter meer positieve en negatieve symptomen dan de adolescenten met MCDD. Ervan uitgaand dat de nonspecifieke basissymptomen over het algemeen eerst ontstaan, gevolgd door positieve en later negatieve symptomen, lijkt de ARMS groep daarmee dichter bij een mogelijke transitie naar psychose te zijn dan de MCDD groep. Dit heeft mogelijk te maken met het feit dat de ARMS groep gemiddeld ouder was en dus dichter bij de leeftijd waarop psychotische stoornissen meestal voor het eerst tot uiting komen. Als tweede stap in het vergelijken van de hoog-risico groepen op mogelijke kwetsbaarheidindicatoren voor psychoses, richtten we ons op neurocognitieve en gedragsmatige kwetsbaarheidindicatoren voor schizofrenie die regelmatig worden gerapporteerd in de literatuur, namelijk beperkingen in het verbaal geheugen, het psychomotorische functioneren, verschillende executieve functiedomeinen en het sociaal functioneren. Daarbij verwachtten we dat beide hoog-risico groepen beperkingen zouden laten zien op al deze gebieden in vergelijking met gezonde controles. Echter, omdat de MCDD groep per definitie beperkingen in het sociale gedrag en/of in de gevoeligheid voor sociale signalen heeft en de ARMS groep niet, verwachtten we meer sociale beperkingen in de MCDD groep dan in de ARMS groep. In Hoofdstuk 3 wordt beschreven dat hoewel beide hoog-risico groepen problemen ervaren in hun functioneren op school en in de omgang met vrienden en familieleden, ze relatief weinig problemen lieten zien met betrekking tot hun neurocognitieve functioneren. Beide hoog-risicogroepen hadden lagere scores op taken die aandacht/werkgeheugen en de productie van verbale output (verbal fluency) meten, maar het verschil met de gezonde controlegroep (i.e. de effect-grootte) was slechts klein. Daarnaast hadden beide hoogrisicogroepen een tragere psychomotorische snelheid dan de gezonde controles. Daarbij was de effect-grootte klein in de ARMS groep en middelmatig in de MCDD groep.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 190

Mirjam Sprong | Adolescents at risk of psychosis In de Hoofdstukken 4 en 5 richtten we ons op het tweede doel van de dissertatie, namelijk de exploratie van sociaal-cognitieve beperkingen als mogelijke kwetsbaarheidindicatoren voor psychoses. Sociale cognitie wordt gedefinieerd als de mentale processen die ten grondslag liggen aan sociale interacties, waaronder processen die te maken hebben met de perceptie en interpretatie van de gevoelens, intenties, behoeften en gedragingen van anderen en het genereren van adequate reacties hierop. Voorbeelden van sociaal-cognitieve vaardigheden zijn het vermogen emoties van anderen te herkennen en het vermogen om de mentale staat (bijvoorbeeld ideeen, wensen, behoeften en intenties) van anderen te begrijpen, waardoor men het gedrag van anderen kan verklaren, manipuleren en voorspellen. Dit laatste wordt ook wel Theory of Mind (ToM) genoemd. Meerdere reviews hebben aangetoond dat personen met schizofrenie moeite hebben met het onderscheiden en benoemen van emotionele gezichtsuitdrukkingen. Er zijn ook enkele, zij het inconsistente, aanwijzingen dat het hebben van beperkingen in de verwerking van emoties een mogelijke kwetsbaarheidindicator voor schizofrenie is. In Hoofdstuk 4 testten we de hypothese dat de herkenning van emotionele gezichtuitdrukkingen is aangedaan in adolescenten met een verhoogd risicio op het ontwikkelen van een psychose. In tegenstelling tot wat we verwachtten, maakten beide hoog-risicogroepen over het algemeen niet meer fouten in het herkennen van emoties dan gezonde controles. De MCDD groep bleek echter specifieke problemen te hebben met het herkennen van de emotie angst. Ook was de informatieverwerkingssnelheid van de MCDD groep op alle visuele informatieverwerkingstaken trager, met kleine tot middelgrote effect-groottes. Omdat deze problemen ook worden gerapporteerd bij kinderen met PDD(-NOS), lijkt het er op dat deze zijn te relateren aan het PDD spectrum en niet specifiek aan MCDD. De “building-block view” van sociale cognitie stelt dat adequate “lagere orde” ofwel niet-sociaal cognitieve vaardigheden een voorwaarde – maar niet perse voldoende – zijn voor “hogere orde”, ofwel sociaal-cognitieve vaardigheden. In Hoofdstuk 4 lieten we zien dat aandacht/werkgeheugen en de verwerking van abstracte visueel-ruimtelijke informatie en van neutrale gezichten elk bijdragen aan de hoeveelheid verklaarde variantie in de herkenning van emotionele gezichtsuitdrukkingen. Dit is in overeenstemming met de building block view en suggereert dat de herkenning van emotionele gezichtsuitdrukkingen mogelijk beter kan worden beschouwd als een combinatie van neurocognitive vaardigheden dan als een specifieke vaardigheid. Bij de start van het onderzoek in 2002 waren er meerdere studies waarin werd gerapporteerd dat personen met schizofrenie vaker moeite hebben om de mentale staat van anderen in te schatten en te gebruiken om hun gedrag te verklaren of te voorspellen (ToM). De vraag rees bij ons of een beperking in ToM mogelijk een kwetsbaarheidindicator was voor psychose en dus aantoonbaar was voorafgaand aan

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 191

Mirjam Sprong | Adolescents at risk of psychosis het ontstaan van de eerste psychotische episode. We besloten om eerst een metaanalyse uit te voeren om een inschatting te maken van de effect-grootte van de ToM beperkingen in personen met schizofrenie. De resultaten van deze meta-analyse (Hoofdstuk 5) laten zien dat personen met schizofrenie significant vaker fouten maken op taken die ToM beogen te meten dan gezonde controles en dat het verschil tussen patiënten met schizofrenie en gezonde controles groot is (geschatte effect-grootte d = -1.255; 95% betrouwbaarheidsinterval: -1.441 to -1.069). Bovendien blijken ook patienten van wie de symptomen van schizofrenie in remissie zijn meer moeite met ToM taken te hebben dan gezonde controles. Dit suggereert dat ToM beperkingen niet alleen aanwezig zijn in de accute fase van de ziekte, maar trait-afhankelijk zijn. Dit wordt ondersteund door studies waarin wordt gerapporteerd dat ToM beperkingen ook aanwezig zijn in mensen met een genetisch verhoogd risico op schizofrenie en dat er een relatie is tussen ToM beperkingen en het hebben van schizotypische persoonlijkheidstrekken. Samengevat (Hoofdstuk 6), beide hoog-risico groepen rapporteren hoog-risico symptomen, schizotypische persoonlijkheidstrekken en sociale problemen en verschillen daarin alleen van elkaar met betrekking tot de positieve en negatieve mogelijkprodromale symptomen. Ondanks deze problemen laten beide hoog-risico groepen op de meeste neurocognitieve taken nauwelijks problemen zien. Wel presteren beide groepen vergeleken met gezonde controles minder goed op taken die psychomotorische snelheid, aandacht/werkgeheugen en de productie van verbale output (verbal fluency) meten. Dit betekent dat beperkingen op deze neurocognitieve domeinen mogelijk kwetsbaarheidindicatoren zijn voor psychose. Voorts toonden we aan dat van de sociaal-cognitieve domeinen, beperkingen in ToM, maar niet in de herkenning van emoties mogelijke kwetsbaarheidindicatoren voor psychose zijn.

4. Discussie In Hoofdstuk 6 worden een aantal mogelijke oorzaken van de veelal negatieve bevindingen met betrekking tot de hypothesen betreffende de neurocognitive kwetsbaarheidindicatoren besproken. Wij denken dat deze mogelijk kunnen worden verklaard door: (a) het feit dat de deelnemers aan onze studies jonger waren dan in de meeste andere ARMS studies, (b) het feit dat er (mede daardoor) mogelijk sprake was van hoge percentages valspositieven (i.e. adolescenten die wel voldoen aan de onderzoekscriteria voor hoog-risico, maar die geen transitie zullen maken naar psychose) in beide hoogrisico-groepen, en

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 192

Mirjam Sprong | Adolescents at risk of psychosis (c)

het feit dat medicatiegebruik geen exclusiecriterium was en vaak voorkwam in de hoog-risicogroepen. (d) Daarnaast zijn er een aantal methodologische beperkingen aan de studies in deze dissertatie, zoals het feit dat er demografische verschillen waren tussen de groepen. De belangrijkste beperking van dit proefschrift is echter dat er in deze dissertatie alleen cross-sectionele data worden gepresenteerd. Follow-up van de deelnemers is noodzakelijk om te bepalen wie uiteindelijk een psychotische episode zal ontwikkelen. Tot die tijd is feitelijk onbekend of de hoog-risico adolescenten daadwerkelijk een hoogrisico hebben op het ontwikkelen van een psychotische episode. Ook kan pas na followup de predictieve validiteit van de hoog-risico symptomen, schizotypische persoonlijkheidstrekken, sociale problemen en beperkingen in psychomotorische snelheid, aandacht/werkgeheugen en de productie van verbale output worden bepaald. Ten slotte, het feit dat er in de hoog-risico groepen geen beperkingen werden gevonden op de meeste neurocognitieve domeinen sluit niet uit dat deze kwetsbaarheidindicatoren kunnen zijn voor psychose. Immers, sommige beperkingen worden mogelijk pas zichtbaar wanneer het moment van transitie naar psychose nadert. Daarnaast is het percentage vals-positieven mogelijk te hoog om een onderscheid te maken tussen de hoog-risico groepen en de gezonde controles. De onderzoeksdata die zijn verzameld tijdens de hermetingen vormen de basis voor een tweede dissertatie, welke in de komende tijd zal worden gepubliceerd.

5. Aanbevelingen voor toekomstig onderzoek Er is momenteel nog te weinig bekend over de psychometrische eigenschappen van de instrumenten waarmee de ARMS deelnemers worden geselecteerd en de mogelijkprodromale symptomen worden gemeten. Tot dus ver zijn voornamelijk voorlopige resultaten met betrekking tot de predictieve validiteit voor de transitie naar psychose gepubliceerd, terwijl er weinig bekend is over de sensitiviteit en specificiteit van deze instrumenten, noch van de betrouwbaarheid in jonge deelnemers. Toekomstige studies zouden zich moeten richten op deze psychometrische eigenschappen. Daarnaast zou meer aandacht moeten worden besteed aan het combineren van verschillende risicosymptomen en -factoren, zodat de identificatie van personen met een hoog risico op het ontwikkelen van een psychotische episode nauwkeuriger wordt. Daarbij kan men bijvoorbeeld denken aan het meten van negatieve symptomen. Ook zou er meer aandacht moeten komen voor het rechtstreeks vergelijken van potentiële kwetsbaarheidindicatoren voor psychose in andere populaties met een hoogrisico op psychose, zoals personen met een genetisch risico op het ontwikkelen van schizofrenie, Klinefelter syndroom, 22q11-deletie syndroom of cluster A

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 193

Mirjam Sprong | Adolescents at risk of psychosis persoonlijkheidsstoornissen. Naast neurocognitieve en gedragsmatige kwetsbaarheidindicatoren, zou men zich daarbij ook moeten richten op andere andere potentiële kwetsbaarheidindicatoren voor psychose, waaronder genetische markers en andere biologische kwetsbaarheidindicatoren zoals structurele en functionele hersenafwijkingen. Op die manier wordt bijgedragen aan de zoektocht naar de vele verschillende oorzaken van psychoses, met als uiteindelijke doel een betere behandeling en prognose van mensen die daaraan lijden.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 194

Mirjam Sprong | Adolescents at risk of psychosis

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 195

Mirjam Sprong | Adolescents at risk of psychosis

Dankwoord

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 196

Mirjam Sprong | Adolescents at risk of psychosis

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 197

Mirjam Sprong | Adolescents at risk of psychosis Op de eerste plaats wil ik alle deelnemers en hun ouders bedanken voor alle tijd en energie die ze staken in dit onderzoek. Steeds weer waren jullie bereid om nòg een vragenlijst in te vullen of nòg een keer naar het UMC te komen voor een interview, MRI scan of ERP afname, terwijl jullie er zo weinig voor terug kregen. Jullie persoonlijke verhalen hebben grote indruk op me gemaakt en zullen me nog lang bijblijven. Ook de verwijzers en behandelaars zijn van onmetelijk belang geweest voor dit onderzoek. Zonder jullie zouden er immers maar weinig deelnemers zijn geweest en dus geen onderzoek. Ik wil met name de teamleiders van Altrecht Jeugd en de mensen van het Psychosespreekuur van de afdeling Kinder- en Jeugdpsychiatrie van het UMC bedanken voor hun toestemming de intakebesprekingen bij te wonen en de intakeverslagen door te nemen. Beste Herman, ik wil je bedanken dat je dit onderzoek mogelijk hebt gemaakt. Het was niet altijd makkelijk voor me om door de - vaak door mijzelf aangeplante - bomen het bos te zien, maar jouw adelaarsblik bracht me altijd weer op het juiste spoor. Patricia, beste copromotor, jij was de afgelopen jaren altijd bereikbaar voor praktische adviezen en snelle feedback. Tijdens het soms moeizame begin van het onderzoek heb ik veel aan je steun en daadkracht gehad. Bovendien heb je me het vertrouwen gegeven dat mijn eigen ideeën vaak niet eens zo slecht zijn. Hanna, jij wist me - eerst als copromotor en later als promotor - altijd het enthousiasme voor mijn data terug te geven als ik dat even kwijt was. Onze besprekingen hebben de artikelen in dit proefschrift tot een hoger niveau gebracht. De DUPS-onderzoekers van het AMC, tevens medeauteurs, Don Linszen, Peter Dingemans en Hiske Becker, wil ik bedanken voor de prettige samenwerking. Ik wens jullie veel succes met de verdere verwerking van de data en blijf graag op de hoogte van jullie resultaten. Ook de overige medeauteurs, Bertine, Leo en Joop, bedankt voor jullie waardevolle bijdragen aan de artikelen in dit proefschrift. Beste Tim, aan jou de niet zo gemakkelijke taak “mijn borduurwerk” verder af te maken. Gelukkig is die taak aan jou wel toevertrouwd. Bedankt voor de fijne samenwerking, interessante discussies, collegialiteit en (schrijf-)adviezen. Het was erg fijn om je de afgelopen jaren als klankbord te hebben mogen gebruiken. Petra en Anneke, lieve onderzoeksassistentes: wat hebben jullie hard gewerkt! Ik ben jullie enorm dankbaar voor jullie enthousiasme, inzet en flexibiliteit. Dankzij jullie humor en persoonlijke benadering kwamen de meeste jongeren graag terug voor hun hermetingen. Petra, jij schijnt eens te hebben gezegd: “Mirjam bedenkt het en ik voer het uit”. Bij deze wil ik dat nog even recht zetten. Vanaf het moment dat je bij het DUPS-onderzoek kwam werken, heb je altijd actief meegedacht en we hebben samen vele kinderziektes opgelost. Lieve Anneke, we hebben je in het diepe gegooid en jij begon vrolijk en onvermoeibaar te zwemmen. Je was altijd weer bereid om me te helpen een deadline te halen, bijvoorbeeld door het invoeren van data of het uitpluizen van dossiers. Jullie beiden bedankt, voor alles.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 198

Mirjam Sprong | Adolescents at risk of psychosis Stagiaires Nicole en Anne, bedankt voor jullie hulp bij de dataverzameling en dataverwerking. Ellen, ik zag als een berg op tegen de meta-analyse, maar jij hebt de eerste treden voor me uitgehakt, waardoor de rest van de beklimming een stuk gemakkelijker ging. Lieve Mariëlle, we hebben de afgelopen jaren heel wat lief en leed met elkaar mogen delen. Ik heb veel van je geleerd, onder andere over statistiek (we moeten Andy Field maar eens een bloemetje sturen) en neuropsychologie. We hebben veel gelachen, maar ook vond ik bij jou steun en begrip als ik eens even lekker mijn hart wilde luchten. We moeten gauw weer eens een “grote koffie” gaan drinken. Dankjewel dat je mijn paranimf wil zijn. Het afgelopen jaar heb ik voornamelijk thuis gewerkt, waardoor ik het hebben van leuke kamergenoten extra heb leren waarderen. Celina, Barbara en Carolina, lieve kamergenoten van het eerste uur: jullie hebben mij op weg geholpen op de afdeling en in onderzoeksland. Emmie, jij hebt in de beginperiode ook heel wat ERPs afgenomen voor het DUPS-onderzoek, maar ik leerde je pas kennen toen je een kamergenoot van me werd. Jullie allemaal bedankt voor jullie hulp, steun en belangstelling en voor de gezellige lunches en etentjes. Alle overige aio’s, onderzoekers, onderzoeksassistenten, secretaresses en andere medewerkers van de afdeling Kinder- en Jeugdpsychiatrie (en nu soms daarbuiten) wil ik bedanken voor de praktische adviezen en goede sfeer op de afdeling. Speciaal wil ik daarbij noemen Mijke, Maurice, Irene, Jolijn, Selene en Hilde met wie ik af en toe gezellig kon bijkletsen, op de afdeling, een AIO-bijeenkomst of een congres. Meiden, jammer dat ik jullie niet wat beter heb leren kennen. Maurice, het was leuk om met jou Boston te verkennen en om in deze laatste fase samen het wiel opnieuw uit te vinden. Lieve moe, u heeft me gesteund en gestimuleerd in al mijn keuzes, waardoor ik dit alles heb kunnen bereiken. Ik had nog zoveel meer van u willen leren en met u willen delen. Ik mis u nog altijd. Lieve broer Hein, voor jou was het zó vanzelfsprekend dat ik na het VWO naar de universiteit ging, dat je me hoogstpersoonlijk hebt ingeschreven bij de faculteit Sociale Wetenschappen van de Universiteit Utrecht. Ook twijfelde je er nooit aan dat ik dit promotieonderzoek zou afronden, al deed ik dat zelf soms wel. Heel erg bedankt voor je vertrouwen in mij. Ik ben er trots op dat jij mijn paranimf wil zijn en nee, je hoeft niet hetzelfde aan als Mariëlle! Lieve oom Piet en tante Eef, dankzij jullie onvoorwaardelijke steun had ik een zorgeloze studietijd. Bedankt voor de getoonde interesse tijdens mijn studie, maar ook tijdens mijn promotieonderzoek (hopelijk kan ik straks wel een zinnig antwoord geven op de vraag: “Wat is je conclusie?”). Lieve Servaas, Marieke, Kees, Marwytske, Emile, Marieke V. (bedankt voor de prachtige

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 199

Mirjam Sprong | Adolescents at risk of psychosis omslag!), Floor, Diederik, Ine, Timo, Nienke, Guido en Alies. Bedankt voor alle bezoekjes, films, spelletjesmiddagen, shopping, etentjes, uitjes enz. Ik wilde weliswaar nooit over mijn werk praten, maar waardeerde jullie belangstelling zeer. Jeroen, mijn allerliefste, al noem ik je als laatste, je staat voor mij altijd op de eerste plaats. Jij zorgde er de afgelopen jaren voor dat ik er weinig zin in had om in de avonden en weekenden achter mijn computer te kruipen, maar tegelijkertijd zorgden jouw onaflatende steun en relativeringsvermogen (“het wordt altijd weer 6 uur”) er voor dat het boekje uiteindelijk toch afgekomen is. Dank je wel dat je er altijd voor me bent.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 200

Mirjam Sprong | Adolescents at risk of psychosis

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 201

Mirjam Sprong | Adolescents at risk of psychosis

Curriculum Vitae

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 202

Mirjam Sprong | Adolescents at risk of psychosis

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 203

Mirjam Sprong | Adolescents at risk of psychosis Mirjam Sprong werd geboren op 19 september 1975 in Rotenburg (Duitsland). In 1994 behaalde zij haar VWO diploma aan het Christelijk College Nassau Veluwe in Harderwijk. Na een jaar te hebben gewerkt als au-pair in een buitenwijk van Chicago, begon ze met haar studie psychologie aan de Universiteit Utrecht. In 2001 studeerde ze af met als specialisatie Klinische en Gezondheidspsychologie. Aansluitend werkte ze gedurende anderhalf jaar als psychodiagnostisch medewerker en onderzoeksassistent op de afdeling Psychologisch Onderzoek van de Stichting GGZ Meerkanten in Ermelo. In september 2002 startte ze haar promotieonderzoek naar mogelijke kwetsbaarheidindicatoren voor psychoses op de afdeling Kinder- en Jeugdpsychiatrie van het Universitair Medisch Centrum in Utrecht. Daarbij volgde ze het promovendi programma van de Graduate School van het Rudolf Magnus Instituut voor Neurowetenschappen. De resultaten van haar promotieonderzoek zijn beschreven in dit proefschrift.

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 204

Mirjam Sprong | Adolescents at risk of psychosis

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 205

Mirjam Sprong | Adolescents at risk of psychosis

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 206

Mirjam Sprong | Adolescents at risk of psychosis

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 207

Mirjam Sprong | Adolescents at risk of psychosis

Universiteit_Proefschrift

29-04-2008

11:29

Pagina 208

Mirjam Sprong | Adolescents at risk of psychosis