Developmental vulnerability to psychosis: Selective aggregation of basic self-disturbance in early onset schizophrenia

SCHRES-07845; No of Pages 6 Schizophrenia Research xxx (2018) xxx–xxx

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Developmental vulnerability to psychosis: Selective aggregation of basic self-disturbance in early onset schizophrenia Andrea Raballo a,b,⁎,1, Elena Monducci c,1, Mauro Ferrara d, Paolo Fiori Nastro c, Claudia Dario c,e,f, on behalf of RODIN group a

Psychodiagnostic and Clinical Psychopharmacology Unit, Division of Psychiatry, Clinical Psychology and Rehabilitation, Department of Medicine, University of Perugia, Perugia, Italy Psychopathology and Development Research Group, Norwegian University of Science and Technology (NTNU), Trondheim, Norway Department of Neurology and Psychiatry, “Sapienza” University of Rome, Rome, Italy d Pediatrics and Paediatric Neuropsychiatry, “Sapienza” University of Rome, Rome, Italy e Psychiatric Center Hvidovre, University of Copenhagen, Denmark f Center for Subjectivity Research, University of Copenhagen, Denmark b c

a r t i c l e

i n f o

Article history: Received 1 February 2018 Received in revised form 6 May 2018 Accepted 12 May 2018 Available online xxxx Keywords: Self-disorder Schizophrenia Early onset psychosis Ultra High Risk (UHR) Adolescence Early detection

a b s t r a c t Trait-like anomalies of subjective experience (aka, Basic Self-disturbance or Self-disorder, SD) have been empirically identified as schizophrenia-specific markers of vulnerability in several clinical and genetic high-risk populations. However, such specificity is still to be tested in developmental years, where emerging psychopathology is less crystallized and diagnostic boundaries more blurred. Thus, the current study explores the distribution of SD in adolescent help-seekers (age range 14 to 18) and tests the specificity of SD with respect to the severity of their diagnostic staging (Early Onset schizophrenia-spectrum psychosis [EOP], ultra high-risk [UHR] and clinical helpseeking controls [CHSC]). For this purpose, 96 help-seeking adolescents consecutively referred to specialized Child and Adolescent Units for diagnostic evaluation, underwent a comprehensive psychopathological examination including the specific interview for SD (i.e. the Examination of Anomalous Self-Experience, EASE). One-way ANOVA was used to test the diagnostic distribution of SD (EASE score), whereas multinomial logistic regression was used to test the effect of SD on the diagnostic outcome. SD frequency (both in terms of EASE total score and domain sub-scores) was decreasing progressively from EOP to CHSC, with intermediate levels in UHR. The EASE total score increased the risk of belonging to the more severe diagnostic stages (i.e, UHR and EOP vs CHSC as reference class) and allowed the correct reclassification of the 75% of the sample. The results confirm the schizophrenia-spectrum specificity of SD in adolescence, highlighting their potential value for early differential diagnosis and risk stratification. © 2018 Elsevier B.V. All rights reserved.

1. Introduction Trait-like anomalies of subjective experience (aka, Basic Selfdisturbance or Self-disorder, SD) have been empirically identified as schizophrenia-specific markers of vulnerability in several clinical and genetic high-risk populations (Parnas et al., 2003, 2005a, 2011; Maggini and Raballo, 2004; Raballo and Maggini, 2005; Raballo and Parnas, 2011, 2012; Raballo et al., 2011, 2016; Haug et al., 2012; Nelson et al., 2012; Koren et al., 2013, 2016; Nordgaard and Parnas, 2014). Concretely, SD include a panoply of subtle experiential anomalies, such as varieties of depersonalization, fading sense of existing as

⁎ Corresponding author at: Department of Medicine, Division of Psychiatry, Clinical Psychology and Rehabilitation, University of Perugia, Piazzale Lucio Severi 1, 06132 Perugia, Italy. E-mail address: [email protected] (A. Raballo). 1 Shared first-authorship.

an incarnated subject, loss of immediate grasp on perceptual experiences, hyper-reflexivity and sensed alienation from the shared social world (Parnas et al., 2005b; Henriksen and Parnas, 2014; Raballo, 2012) that often antedate the development of major schizophrenia spectrum conditions (Parnas et al., 2011; Sass, 2014). SD, which typically emerge in late childhood and early adolescence (Møller and Husby, 2000; Parnas and Handest, 2003; Saks, 2007) are amenable to reliable clinical assessment through the Examination of Anomalous Self-Experience (EASE) (Koren et al., 2013, 2016; Raballo et al., 2016; Parnas et al., 2005b; Møller et al., 2011) and have been proved of potential impact for the purpose of early identification of schizophrenia spectrum conditions among help-seeking subjects (Nelson et al., 2012; Koren et al., 2013; Raballo et al., 2016). However, such specificity is still to be empirically tested in developmental years, when emerging psychopathology is less crystallized, diagnostic boundaries more blurred and overall clinical decision making more complicated (Preti et al., 2012).

https://doi.org/10.1016/j.schres.2018.05.012 0920-9964/© 2018 Elsevier B.V. All rights reserved.

Please cite this article as: Raballo, A., et al., Developmental vulnerability to psychosis: Selective aggregation of basic self-disturbance in early onset schizophrenia, Schizophr. Res. (2018), https://doi.org/10.1016/j.schres.2018.05.012

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A. Raballo et al. / Schizophrenia Research xxx (2018) xxx–xxx

For example, age 14–18 is the peak symptomatic age for several conditions, ranging from Early onset schizophrenia and related nonaffective psychoses (EOP) (i.e. a group of severe debilitating disorders, typically characterized by insidious onset in adolescence and poorer outcome (Veru et al., 2016)) to other neurodevelopmental disorders, broadly defined at risk mental states and generic help-seeking (Vyas et al., 2011; Cannon et al., 2003; Raballo et al., 2014). Therefore, early differential diagnosis of adolescent help-seekers is particularly troublesome. To address such complexity contemporary research emphasizes the primacy of a staging approach (Raballo and Larøi, 2009; McGorry et al., 2003; Schultze-Lutter et al., 2015) which currently integrates a combination of operational definitions (Schultze-Lutter et al., 2015). Among those, the Ultra High Risk (UHR) Criteria, proposed by McGorry and colleagues (Yung et al., 2003) on the basis of the DSM IV, define three sub-syndromal conditions of important pragmatic value (Nelson et al., 2013). Briefly, UHR status is conferred to young help-seekers that present a certain combination of 1) attenuated psychotic symptoms (APS) or 2) fully articulated psychotic symptoms if of transient duration (BLIPS: brief, self-limited, intermittent psychotic symptoms), and/or 3) functional decline with a clinical diagnosis of Schizotypal Personality Disorder or a first-degree relative with any psychotic disorder (State-Trait vulnerability, STV) (Yung and Nelson, 2013; Correll et al., 2010). Therefore, the aim of the present study is two-fold: first, we wished to test the schizophrenia-spectrum specificity of basic self-disturbance (SD) in a sample of symptomatic, help-seeking adolescents; second, we wished to check SD potential for early differential severity staging (i.e. to separate clinical help-seeking vs UHR vs EOP). For this purpose, we stratified a sample of 96 help-seeking in three diagnostic groups of decreasing severity: a) early onset schizophreniaspectrum psychosis (EOP), b) Ultra High Risk (UHR) for psychosis, and c) help-seekers not meeting EOP or UHR status (thereby termed Clinical Help-Seeking Controls, CHSC). Based on available empirical research (Parnas et al., 2003, 2005a, 2011; Maggini and Raballo, 2004; Raballo and Maggini, 2005; Raballo and Parnas, 2011, 2012; Raballo et al., 2011, 2016; Haug et al., 2012; Nelson et al., 2012; Koren et al., 2013, 2016; Nordgaard and Parnas, 2014) we expected SD to: 1) Selectively aggregate in the EOP group, with the following quantitative gradient: EOP N UHR N CHSC; 2) Increase the odds of belonging to the more advanced staging groups (i.e. UHR and EOP) as compared to CHSC; 3) Allow to the correct reclassification of cases into the original diagnostic staging classes; in particular we expected SD to optimize the correct classification of EOP (higher SD and overt psychosis) and CHSC (lower SD and no immediate risk of psychosis), while being less discriminant for UHR. By definition, indeed, this group encompasses a set of sub-syndromal precursors of overt psychosis, is expected to have intermediate level of SD and is conceptualized as diagnostically pluripotent in terms of outcomes (i.e. it is less diagnostically stable) (Nelson et al., 2011; Yung et al., 2012). 2. Materials and methods 2.1. Sample 96 adolescents, consecutively admitted to two specialized ChildAdolescent facilities (the Complex Child and Adolescent Neurology and Psychiatry Operative Unit of the “Sapienza” University of Rome Department of Pediatrics; and the Child Neuropsychiatry Unit of the Department Bambino Gesù Children's Hospital). These two facilities operate as expert referral centres for general practitioners as wall as for more peripheral neuropsychiatric institutions in the greater area of Rome and the South of Italy. Thus, all the referred adolescents (aged between 14 and 18 years) had already been in contact with a local, primary psychiatric facility or specialist that then required further

diagnostic evaluation. The current sample was enrolled over a period of 18 months, starting from January 2013, independently of their initial clinical diagnosis at admission. Besides age, inclusion criteria were: IQ N 70, fluency in Italian, absence of organic brain disorder and/or severe primary substance abuse as clinically dominating comorbid condition. Likewise, severely aggressive or involuntarily admitted patients were excluded because of ethical concerns or because they were considered to be unable to undergo the full examination. The study was approved by the relevant Medical Ethics Committee and the patients were recruited upon written informed consent from child and his/ her parents or guardian. Of the 104 initially referred subjects, 8 refused to give consent to participate in the assessment, so that the final sample included 96 adolescents, 38 males and 58 females with the average age of 15.5 years (SDs = 1.2). The majority of the participants (81.2%) received a treatment (either pharmacological, psychotherapeutic or a combined therapy), whereas perinatal distress and developmental disorders were observed in the 14.6% and 13.5% of all patients respectively (see Table 1 for details). 2.2. Assessment procedure All the participants underwent a brief interview to collect sociobiographical information, medical history, developmental disorders, previous or current pharmacological and/or psychotherapeutic treatment, and family history. A comprehensive psychiatric diagnostic evaluation was conducted including the Kiddie-Schedule for Affective Disorders and Schizophrenia for School Aged Children - Present and Lifetime Version, (K-SADS-PL) (Kaufman et al., 1997). The final DSM-IV TR diagnosis was assigned through consensus between the interviewers and the clinicians in charge. The presence of the Ultra High Risk Syndrome was evaluated using the Structured Interview for Prodromal Syndromes/Scale of Prodromal Symptoms (SIPS/SOPS) (McGlashan et al., 2001). The SIPS is a structured diagnostic interview used to diagnose the three prodromal syndromes. The SIPS includes the SOPS, the Schizotypal Personality Disorder Checklist (APA 1994), a family history questionnaire (Andreasen et al., 1977) and a version of the Global Assessment of Functioning scale (GAF) (Hall, 1995). The SIPS also includes operational definitions of the three prodromal syndromes. Social and role (academic/work) functioning was assessed with the Global Functioning: social (GF:SS) and the Global Functioning: role (GF:RS) scales (Cornblatt et al., 2007; Lo Cascio et al., 2017). SD was assessed with the Examination of Anomalous Selfexperience (EASE) (Parnas et al., 2005b), a specific interview encompassing five main domains: (1) cognition and stream of consciousness (such as experiences of thought interference, thought block, thought pressure, and spatialization of thinking); (2) selfawareness and presence (such as unstable first person perspective, lack of basic, immediate sense of identity or “mineness,” diminished self-presence); (3) bodily experiences (such as somatic depersonalization and sense of mind-body misfit or disconnection); (4) demarcation/transitivism (such as passivity mood and various manifestations of failing of self-world boundary); and (5) existential reorientation (such as development of quasi-metaphysical world views or solipsistic experiences). To ensure comparability with previous and on-going studies with the EASE and analogue instruments (Parnas et al., 2003; Nordgaard and Parnas, 2014; Møller et al., 2011; Skodlar and Parnas, 2010; Vollmer-Larsen et al., 2007), each EASE item was dichotomously recoded as 0 (absent) or 1 (present). All interviewers (GC, CD, NG, NLC, EM) were trained under the supervision of Dr. Josef Parnas (the main author of the EASE) at the Psychiatric Center in Hvidovre, University of Copenhagen, Denmark, and followed up by AR, certified EASE instructor for Italy (http://easenet.dk/certification/). Likewise, the interviewers were trained in administrating SIPS. The average duration of the entire interview was between 2 and 5 h, with the EASE covering approximately half of that time. For the purpose of data analyses, we used the diagnostic information (clinical diagnosis

Please cite this article as: Raballo, A., et al., Developmental vulnerability to psychosis: Selective aggregation of basic self-disturbance in early onset schizophrenia, Schizophr. Res. (2018), https://doi.org/10.1016/j.schres.2018.05.012

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Table 1 Socio-demographic characteristics of the sample.

N Gender M (%) F (%) Age Mean (SD) Median (Range) No treatment (%) Drug therapy only (%) Psychotherapy only (%) Combined treatment (%) Drug therapy (%) Antipsychotics (%) Antidepressants (%) Anxiolytic (%) Anticonvulsants (%) Psychostimulants (%) Birth injuries Yes (%) Developmental disorder Yes (%)

Sample

EOP

UHR

CHSC

96

13

23

60

38 (39.6) 58 (60.4)

5 (38.5) 8 (61.5)

11 (47.8) 12 (52.2)

22 (36.7) 38 (63.3)

χ 2 = 0.87; p = .646

15.5 (1.2) 16 (13.18) 19 (19.8) 9 (9.4) 24 (25.0) 44 (45.8) 53 (55.2) 36 (37.3) 27 (28.1) 18 (18.7) 13 (13.5) 1 (1.0) 14 (14.6)

15.7 (1.6) 16 (13.18) 2 (15.4) 1 (7.7) 2 (15.4) 8 (61.5) 9 (69.2) 8 (61.5) 4 (30.8) 3 (23.0) 6 (46.1) 0 (0.0) 1 (7.7)

15.6 (1.2) 16 (13.18) 4 (17.4) 2 (8.7) 4 (17.4) 13 (56.5) 15 (65.2) 10 (43.5) 6 (26.1) 5 (21.7) 2 (8.7) 0 (0.0) 4 (13.3)

15.5 (1.3) 16 (13.18) 4 (6.7) 2 (3.3) 4 (6.7) 13 (21.7) 29 (48.3) 18 (30.0) 17 (28.3) 10 (16.7) 5 (8.3) 1(1.7) 9 (15.0)

χ 2 = 6.34; p = .785

13 (13.5)

1 (7.7)

6 (26.1)

6 (10.0)

χ 2 = 4.0; p = .679

χ 2 = 2.28; p = .319 χ 2 = 1.55; p = .460⁎ χ 2 = 0.01; p = .996⁎⁎ χ2 = 10.48;p = .005⁎⁎⁎ χ 2 = 0.64; p = .722 χ 2 = 4.11; p = .127

⁎ p ≤ .05. ⁎⁎ p ≤ .01. ⁎⁎⁎ p ≤ .001.

according to DSM-IV TR and SIPS) to divide the sample into 3 clinical diagnostic groups: 1) early onset Schizophrenia spectrum psychosis (EOP), n = 13, which includes all the subjects receiving a diagnosis of non-affective psychosis (i.e. schizophrenia, n = 5; schizophreniform disorder, n = 1; schizoaffective disorder, n = 1 and psychosis NOS, n = 6)); 2) Ultra high-risk of psychosis (UHR), n = 23 (of which 22 APS and 1 BLIPS), and 3) clinical help-seeking controls (CHSC) who did not met the criteria for EOP or UHR, n = 60. The clinical diagnoses for the CHSC were mood disorders (n = 31), anxiety disorders (n = 16), eating disorders (n = 7), conduct disorder (n = 4), Asperger disorder (n = 1), and Tourette disorder (n = 1). 2.3. Statistical analysis Chi-square test was used to compare the distributions of sociodemographic and medical variables. Between-group comparisons of continuous rank-scaled variables were analysed using Kruskal-Wallis tests. Mann-Whitney U tests were used for post-hoc pairwise comparisons of the three groups. Correlational analysis with Spearman's rho was used to test associations across scales scores. Multinomial logistic regression, with diagnostic staging (CHSC, UHR, EOP) as the dependent variable, was applied to test the hypothesis that SD would increase the likelihood of a higher diagnostic severity. In terms of classification performance (i.e. classification accuracy which compares predicted group membership based on the logistic model to the actual CHSC, UHR, EOP status), the benchmark to characterize the multinomial logistic regression model as useful is a 25% improvement over the rate of accuracy achievable by chance alone. The latter is determined by squaring and summing the proportion of cases in each group (i.e. CHSC, UHR, EOP: 0.6772 + 0.2192 + 0.1042 = 51.32%) and therefore the proportional by chance accuracy criterion threshold (i.e. the benchmark threshold indicating that the model has an overall case classifications accuracy at least 25% higher than the proportion by chance rate) is 1.25 ∗ 51.32% = 64.16%. This proportion will be compared with the overall percentage of the final model. The goodness-of-fit was determined using the likelihood ratio test, and the total variance explained was computed using Nagelkerke R2. Multinomial, rather than ordinal, logistic regression was chosen because the proportional odds assumption between the diagnostic outcome groups (CHSC, UHR, EOP) could not be made. All analyses were conducted with SPSS, version 22.

3. Results The sample characteristics are shown in Table 1. The compared groups (EOP, UHR and CHSC) did not differ for gender (p = .646), age (p = .785), previous treatments (p = .673), perinatal distress (p = .722) or developmental disorders (p = .127). SD distribution across the groups is presented in Table 2, together with psychopathological (i.e. SIPS positive, negative, disorganized and general psychopathology domains) and functional scale scores (GF: SS, GF:RS, GAF). Both EASE total and domain sub-scores were higher in EOP, and lower in the CHSC, with intermediate values in UHR. All between group differences were statistically significant. Table 3 presents the correlations between SD (total EASE score), other psychopathological features (i.e. SIPS/SOPS subscores) and functioning scores (GF: SS, GF:RS, GAF) across the sample. SD were weakly to moderately correlated to all SIPS domains (Spearman's rho range: 0.3–0.5) and weakly correlated with role impairment (GF: RO). Multinomial logistic regression with diagnostic staging as outcome and adjusted for age and gender revealed a significant association between SD (EASE total score) and increasing diagnostic severity. Compared with CHSC, the odds of belonging to the UHR and EOP group increased of respectively, 1.35 (95% confidence interval (CI) 1.17–1.56) and 1.81 (95% CI 1.42–2.30), for each unit increase in EASE total score (Table 4). The overall model explained a substantial part of the variance (Nagelkerke pseudo-R2 = 0.60) and correctly classified 75% of the sample, which substantially exceeds the proportional by chance accuracy criteria (64.15% = 1.25 ∗ 51.32%, a benchmark threshold indicating an improvement of at least 25% over the rate of accuracy achievable by chance alone). The subgroup-wise share of correct reclassification based on the level of SD was 61.5% (8/13) for EOP, 43.5% (10/23) for UHR and 90.0% (54/60) for CHSC. The likelihood ratio test (X2 = 67.584) indicated that the full model showed a significantly better fit to the data than the intercept only model (p b .00001). 4. Discussion The study explores the distribution of SD across diagnostically stratified adolescents, divided into three clinical groups: early onset schizophrenia-spectrum (i.e. non-affective) psychosis (EOP), Ultra

Please cite this article as: Raballo, A., et al., Developmental vulnerability to psychosis: Selective aggregation of basic self-disturbance in early onset schizophrenia, Schizophr. Res. (2018), https://doi.org/10.1016/j.schres.2018.05.012

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A. Raballo et al. / Schizophrenia Research xxx (2018) xxx–xxx

Table 2 Distribution of SD (EASE total and domain subscores), psychopathological dimensions (SIPS) and functioning scales (GF:SS, GF:RS, GAF) across the three diagnostic groups. N

EASE total score Cognition and stream of consciousness Self-awareness and presence Bodily experiences Demarcation/transitivism Existential reorientation SIPS positive SIPS negative SIPS disorganized SIPS general Global Functioning Social Scale Global Functioning Role Scale Global Assessment of Functioning

Mean (SD) Median (Range) Mean (SD) Median (Range) Mean (SD) Median (Range) Mean (SD) Median (Range) Mean (SD) Median (Range) Mean (SD) Median (Range) Mean (SD) Median (Range) Mean (SD) Median (Range) Mean (SD) Median (Range) Mean (SD) Median (Range) Mean (SD) Median (Range) Mean(SD) Median (Range) Mean(SD) Median (Range)

EOP

UHR

CHSC

13

23

60

21.0 (6.6) 22 (11; 30) 7.3 (3.8) 9 (0;13) 8.4 (4.0) 9 (3;14) 2.6 (1.3) 2 (1;5) 0.8 (1.1) 0 (0;3) 1.7 (2.2) 0 (0;7) 11.33 (7.1) 12 (0.20) 16.67 (7.9) 18 (2.28) 6.08 (3.5) 6.5 (0.13) 9.00 (5.2) 10 (1.14) 5.1 (1.1) 5 (3; 7) 5.1 (1.1) 5 (3; 7) 38.0 (15.6) 40 (17; 70)

12 (4.5) 13 (4;21) 6.3 (2.9) 6 (0;10) 3.9 (2.7) 3 (0;9) 0.9 (1.6) 0 (0;6) 0.4 (0.6) 0 (0;2) 0.8 (1.1) 1 (0;4) 10.71 (4.6) 10 (3.22) 13.83 (6.2) 13.50 (2.28) 5.63 (4.0) 4 (1.14) 8.54 (4.3) 8.50 (0.15) 5.6 (1.6) 6 (3; 8) 6.3 (1.1) 6 (4; 9) 46.3 (15.2) 48 (10; 70)

6.3 (4.1) 6 (0; 15) 3.2 (2.4) 3 (0;10) 2.2 (1.9) 2 (0;7) 0.6 (0.8) 0 (0;3) 0.1 (0.3) 0 (0;1) 0.2 (0.6) 0 (0;3) 4.02 (3.2) 4 (0.18) 10.98 (5.9) 11 (0.27) 3.12 (2.4) 2 (0.11) 7.10 (3.8) 8 (1.19) 6.1 (1.4) 6 (3; 9) 6.3 (1.6) 6 (3; 9) 46.3 (15.8) 50 (8; 83)

Kruskal-Wallis test

Mann-Whitney U test

H = 42.16 p b .001⁎⁎⁎ H = 23.02 p b .001⁎⁎⁎ H = 27.29 p b .001⁎⁎⁎

EOP N UHR N CHSC

H = 23.93 p b .001⁎⁎⁎ H = 12.80 p = .002⁎⁎⁎ H = 15.71 p b .001⁎⁎⁎ H = 35.85 p b .001⁎⁎⁎ H = 7.84 p b .020⁎ H = 12.18 p b .002⁎⁎ H = 3.63 p b .162 H = 4.48 p = .106 H = 7.25 p = .027 H = 1.28 p = .527

EOP = UHR N CHSC EOP N UHR N CHSC EOP N UHR = CHSC EOP = UHR N CHSC EOP = UHR N CHSC EOP = UHR N CHSC EOP N CHSC EOP = UHR N CHSC

EOP N CHSC EOP N UHR = CHSC EOP N CHSC

⁎ p ≤ .05. ⁎⁎ p ≤ .01. ⁎⁎⁎ p ≤ .001.

High Risk (UHR) and clinical help-seeking controls (CHSC) who don't suffer from psychotic disorder or UHR condition (but are nonetheless above the clinical-caseness threshold). The assumption of a decreasing gradient of SD from diagnostically more severe condition (i.e. EOP) to broader help-seeking states (CHSC), with UHR in intermediate position was confirmed. Therefore, our results strongly suggest that the distribution pattern, previously reported on adult samples (Raballo et al., 2011; Raballo and Parnas, 2012; Nordgaard and Parnas, 2014; Parnas and Henriksen, 2014), could be generalized to adolescents as well. This is in line with the notion of SD as trait-like experiential features (Nordgaard et al., 2017; Raballo and Preti, 2018a; Nordgaard et al., 2018; Raballo and Preti, 2018b) indexing individuals with the propensity to develop schizophrenia spectrum conditions (Raballo and Parnas, 2011; Raballo, 2009; Parnas, 2011). Likewise, the relatively low frequency of SD in not-at-risk, nonpsychotic subjects (CHSC) is comparable to the one reported for nonschizophrenia spectrum disorders in other studies (Raballo and Parnas, 2012; Haug et al., 2012; Nordgaard and Parnas, 2014). Furthermore, our study confirms that UHR subjects (some of whom might progress to EOP (Yung et al., 2003; Yung and Nelson, 2013)) have higher levels of SD compared to broadly non-psychotic help-seekers (CHSC).

This is in line with other studies on UHR adolescents (Nelson et al., 2012; Koren et al., 2016) and on UHR samples of adolescents and young adults (Raballo et al., 2016; Parnas et al., 2016). Finally, the multinomial logistic regression model confirmed that the level of SD increases the odds of belonging to the UHR or EOP group as compared to CHSC (OR = 1.35 and 1.81 respectively) and allowed a satisfactory reclassification of the 75% of the cases. In particular, the model (EASE total score adjusted for age and gender), successfully classified about 90% of the CHSC and 60% of EOP, but only 40% of UHR. This makes sense since UHR are by definition diagnostically transient, pluripotent syndromes that might or might not progress towards a first episode psychosis (Nelson et al., 2011; Yung et al., 2012). Overall the results are in line with our initial hypothesis, that SD are a trait phenotype indexing schizophrenia spectrum vulnerability in developmental years as well. Clearly, although the complexity of the diagnostic process in real-life clinical practice is irreducible to a multivariate model, we broadly regard these results as a promising proof of concept: SD could be useful for initial staging and early differential diagnosis in adolescent help-seekers. A number of limitations of our study should be noted. First, we operated with a clinical-pragmatic staging concept, considering a-priori EOP,

Table 3 Correlation matrix (Spearman's rho) between SD (EASE), psychopathological dimensions (SIPS) and functioning scores (GF, GAF). EASE total score SIPS positive SIPS negative SIPS disorganized SIPS general GF:Social GF:Role GAF

0.511⁎⁎ 0.306⁎⁎ 0.386⁎⁎ 0.407⁎⁎ −0.180 −0.269⁎⁎ −0.139

SIPS positive

SIPS negative

SIPS disorganized

SIPS general

GF:Social

GF:Role

0.260⁎ 0.528⁎⁎ 0.322⁎⁎ −0.180 −0.051 0.124

0.481⁎⁎ 0.421⁎⁎ −0.605⁎⁎ −0.553⁎⁎ −0.337⁎⁎

0.404⁎⁎ −0.305⁎⁎ −0.391⁎⁎ −0.070

−0.150 −0.261⁎ −0.193

0.326⁎⁎ 0.208⁎

0.341⁎⁎

⁎ p b .05. ⁎⁎ p b .01.

Please cite this article as: Raballo, A., et al., Developmental vulnerability to psychosis: Selective aggregation of basic self-disturbance in early onset schizophrenia, Schizophr. Res. (2018), https://doi.org/10.1016/j.schres.2018.05.012

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Table 4 Multinomial logistic regression: diagnostic staging as outcome variable. Diagnostic staginga

B

Std. error

Wald

df

Sig.

Exp(B)

95% confidence interval for Exp(B)

UHR

0.300 0.078 0.575 0.594 0.079 0.724

0.073 0.220 0.604 0.123 0.363 1.010

16.829 0.125 0.906 23.280 0.047 0.514

1 1 1 1 1 1

0.000 0.724 0.341 0.000 0.828 0.474

1.350 1.081 1.778 1.810 1.082 2.062

1.169 0.702 0.544 1.422 0.532 0.285

EOP

EASE total score Age (years) Genderb EASE total score Age (years) Genderb

1.557 1.665 5.812 2.304 2.202 14.921

Likelihood ratio test (X2 = 67.584, df = 6, p b .00001). a CHSC as reference category for Diagnostic staging. b Male as reference category for gender.

UHR and CHSC as stages of decreasing clinical severity. Second, the small sample size of the EOP group and the lack of a healthy community control of non-help-seeking adolescents partly limit the generalizability of the results. Indeed, our sample consists of symptomatic, help-seeking adolescents referred to specialized diagnostic units (see Methods section), therefore a pre-selection effect cannot be excluded. For example, this is partly visible in the similar GAF scores of the UHR and CHSC subgroup (see Table 1). This indicates that even CHSC group is rather functionally impaired (i.e. it is not comparable to a community control group). However, to some extent this peculiarity further strengthens the potential of SD as a useful candidate tool for early staging of diagnostic severity. Indeed, EASE total score allowed a correct reclassification of 75% of the cases according to the EOP-UHR-CHSC staging. A further limitation is that we adopted the original UHR classification and we did not include basic symptoms-defined at risk states (i.e. the cognitiveperceptive basic symptoms (COPER) criterion and the cognitive disturbances (COGDIS) criterion (Schultze-Lutter et al., 2014, 2015)) so that some of our CHSC while negative for UHR criteria might still be at higher risk of transition to psychosis. In this sense, future research should target a more fine-grained staging including basic symptoms-defined early risk states (Schultze-Lutter et al., 2014, 2015) (aka, COPER and COGDIS). Finally, the present study is based on the baseline evaluation of a larger, still on-going longitudinal project, so that we were not able yet to separate within the UHR group those that would transition to psychosis from those who would remit. In conclusion, this study corroborates the specificity of SD for early onset non-affective psychosis in adolescence, thereby providing pilot support for SD as a core phenotypic marker of schizophrenia spectrum vulnerability (Raballo and Parnas, 2011; Parnas, 2011; Sass and Parnas, 2003; Parnas, 2012) that could be used for differential diagnosis in developmental years as well. Taken together with converging literature (Raballo and Parnas, 2012; Koren et al., 2013, 2016; Nelson et al., 2012; Nordgaard and Parnas, 2014; Raballo et al., 2016) the results of the current study indicate that the integration of SD in contemporary psychosis risk evaluation approaches might empower early differential staging. Role of funding source The original conceptualization of this work was supported by research fellowships from Sapienza University of Rome (to GC, NLC, EM, CB, CD, CG, NG, CM); Brain and Behaviour Research Foundation (21278) and Bambino Gesù Children's Hospital (to MA, MPC, SV); Norwegian University of Science and Technology (NTNU) Onsager Programme in Psychopathology and Development [70440154] (to AR). No funding agency influenced any aspect of the current work. Contributors A. Raballo and E. Monducci designed the study, conceptualized the analyses and jointly structured this manuscript contributing equally to this work. M. Ferrara, C. Dario and P. Fiori Nastro managed the literature searches and analyses and contributed to the interpretation of the results. The Rome Early Detection of Psychosis in Adolescence Collaborative Network (RODIN) includes: N. Lo Cascio, N. Girardi, M. Patanè from the Department of Neurology and Psychiatry, “Sapienza” University of Rome, Rome, Italy; G. Colafrancesco, C. Gabaglio, C. Margarita, I. Ardizzone from the Department of Pediatrics and Neuropsychiatry, “Sapienza” University of Rome, Rome, Italy; C. Battaglia, M. Armando, MP. Casini, S. Vicari from the Department of

Neurosciences and Neurorehabilitation, Bambino Gesù Children's Hospital, Rome, Italy; P. Girardi from the Neurosciences, Mental Health and Sensory Functions (NESMOS) Department, “Sapienza” University of Rome, Rome, Italy. All members of RODIN participated to the study. All authors contributed to and have approved the final manuscript.

Conflict of interest All authors declare that they have no conflicts of interest.

Acknowledgement The authors would like to thank Prof. Josef Parnas for the inspirational support in designing the overarching RODIN protocol.

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Please cite this article as: Raballo, A., et al., Developmental vulnerability to psychosis: Selective aggregation of basic self-disturbance in early onset schizophrenia, Schizophr. Res. (2018), https://doi.org/10.1016/j.schres.2018.05.012