Effects of Early Trauma on Psychosis Development in Clinical High-Risk Individuals and Stability of Trauma Assessment Across Studies: a Review Samantha L

Redman S.L. et al. Archives of Psychology, vol. 1, issue 3, December 2017 Page 1 of 23

RESEARCH ARTICLE

Effects of early trauma on psychosis development in clinical high-risk individuals and stability of trauma assessment across studies: a review Samantha L. Redman1*, Cheryl M. Corcoran, David Kimhy, Dolores Malaspina2 Author Affiliations: Icahn School of Medicine at Mount Sinai, New York, New York, USA *Corresponding Author: Samantha Redman, Icahn School of Medicine at Mount Sinai, Department of Psychiatry, 53 E 96th Street, New York, NY 10128, phone: 212-659-8756, E-mail: [email protected] ______1 First Author 2 Senior Author

Abstract: Early trauma (ET), though broadly and inconsistently defined, has been repeatedly linked to numerous psychological disturbances, including various developmental stages of psychotic disorders. The prodromal phase of psychosis highlights a unique and relevant population that provides insight into the critical periods of psychosis development. As such, a relatively recent research focus on individuals at clinical high risk (CHR) for psychosis reveals robust associations of early life trauma exposures with prodromal symptoms and function in these cohorts. While prevalence rates of ET in CHR cohorts remain consistently high, methodological measures of traumatic experiences vary across studies, presenting potential problems for reliability and validity of results. This review aims to 1) highlight the existing evidence identifying associations of ET, of multiple forms, with both symptom severity and transition rates to psychosis in CHR individuals, 2) present data on the variability among trauma assessments and its implications for conclusions about its relationship with clinical variables, 3) describe cognitive deficits common in CHR cohorts, including perceptual and neurocognitive impairments, and their neural correlates, that may modify the relationship of ET to symptoms, and 4) propose future directions for standardization of trauma assessment in CHR cohorts to better understand its clinical and cognitive correlates.

Key Words: Early Trauma, Clinical High Risk, Psychosis, Trauma Assessment

Introduction one‟s self or other that overwhelms one‟s ability to cope, frequently manifesting as Trauma, while relatively broad by fear, helplessness, or disorganized or interpretation, has been empirically defined agitated behavior (American Psychiatric as a highly stressful event that involves the Association, 2000). While more concrete threat of injury or threat to the integrity of uses of the word tend to reflect incidents of

Copyright © 2017, Archives of Psychology. All rights reserved. http://www.archivesofpsychology.org Redman S.L. et al. Archives of Psychology, vol. 1, issue 3, December 2017 Page 2 of 23 physical threat, violation, or injury, as in the clinical patterns and phenomena observed in cases of sexual abuse, violence, or life- CHR populations, including attenuated threatening situations, the psychological psychotic symptoms, mood disturbances, experience of trauma is, by definition, and behavioral changes, offer a wealth of subjective. Thus, the individualized information for identifying potential risk experience and implications of trauma vary factors that may enhance early intervention by many factors, including a wide range of and possible prevention efforts. The CHR biological and environmental features. paradigm has gained considerable attention Along the spectrum of traumatic life in recent years due to accumulating evidence experiences, early trauma (ET) in childhood that demonstrates its clinical importance, and adolescence has been consistently linked and this paradigm provides researchers with to psychosis in adulthood (Read, van Os, a unique window into a critical Morrison, & Ross, 2005; Spauwen, developmental period in psychotic disorders. Krabbendam, Lieb, Wittchen, & van Os, 2006). Recent literature has considered Investigators have long debated the childhood trauma exposure as a potential respective roles of genetic and precipitator in the pathogenesis of psychosis environmental factors in the etiology of (Falukozi & Addington, 2012; Arseneault et psychosis, though the current consensus al., 2011; Tikka et al., 2013) and as a factor emphasizes a synergistic relationship that shapes the clinical features of the illness between the two. Aside from biological (Ruby et al., 2014; Veras et al., 2017; vulnerability, several socio-environmental Bechdolf et al., 2010; Thompson et al., factors have been found to increase risk for 2010; Thompson et al., 2011). psychosis (Van Winkel, Stefanis, & Myin- Germeys, 2008). Among them, ET is most The “clinical high risk” (CHR) model for consistently linked to negative physical and psychosis risk underscores a series of mental health outcomes later in life genetic and environmental risks factors that (Ashcroft, Kingdon & Chadwick, 2012). are associated with an increased While ET has been studied extensively in vulnerability for developing psychosis relation to psychotic symptoms, the (McGorry, Yung, & Phillips, 2003). specificity of this relationship, especially in Alternatively referred to as the ultra-high- CHR populations, remains unclear. risk (UHR) state for psychosis, inclusion criteria for this population is defined by This review focuses on the extant literature three non-exclusive, internationally on the associations of early exposure to validated conditions: (1) attenuated trauma with symptoms in CHR cohorts. We psychotic symptoms (APS), (2) brief and begin by reporting on the existing evidence limited intermittent psychotic symptoms that identifies ET, of multiple varieties, as a (BLIPS), and (3) genetic risk and consistent component of the CHR profile, deterioration syndrome (GRD) (Fusar-Poli et and its potential relationship to transition al., 2015). The initial concept of the rates to psychosis. We then describe the prodromal state was defined clinically as a methodologies of these studies in respect to period of distress and disturbance that different trauma assessments, outlining the precedes the first psychotic episode, often strengths and weaknesses of different experienced in early teen and young adult assessments, and the ramifications for years (Yung & McGorry, 1996). While the drawing clear conclusions about the majority (approximately 65%) of those relationship of trauma to symptoms. Next, labeled as CHR do not transition to we discuss distinguishable patterns of psychosis (Mayo et al., 2017), a range of trauma type among CHR cohorts and examine the neurobiological, perceptual, and

Copyright © 2017, Archives of Psychology. All rights reserved. http://www.archivesofpsychology.org Redman S.L. et al. Archives of Psychology, vol. 1, issue 3, December 2017 Page 3 of 23 neurocognitive impairments in CHR positive symptoms and ET in their CHR individuals that may confound or modify cohort and Kline et al. (2016) linked ET these associations. Finally, we discuss future broadly to positive symptoms in CHR and research directions in respect to early-psychosis groups. Earlier studies standardization of trauma assessment across explored the association between specific CHR cohorts, and its implication for positive symptoms and various types of understanding mental health outcomes of trauma exposure, finding significant CHR individuals. correlations of childhood trauma with both hallucinations and delusions (Read, van Os, 1. Effects of Trauma on Symptom Morrison, & Ross, 2005). Victims of early Specificity sexual and physical abuse exhibit significantly more positive symptoms, Up to 90% of individuals at CHR for including voices commenting, ideas of psychosis report a lifetime history of reference, thought insertion, paranoid traumatic events and victimization in ideation, mind-reading, and visual childhood (Mayo et al., 2017). When hallucinations, as compared to individuals compared to non-psychiatric controls, CHR with no abuse history (Ross, Anderson, & individuals endorse much higher rates of Clark, 1994). Increased ET has been traumatic events, with a mean prevalence significantly correlated with delusional rate of approximately 85% across CHR thinking, including grandiose thoughts of samples (Addington et al., 2013; Kraan, status and power, feelings of being watched Velthorst, Smit, Haan, & van der Gaag, or followed, and unusual negative thoughts 2015). CHR individuals with trauma regarding the self (Falukozi & Addington, histories exhibit significantly higher 2012). Positive symptoms are strongly transition rates to psychosis than those with linked to increased dopaminergic no reported trauma exposure (Bechdolf et transmission, while early trauma and stress al., 2010). A meta-analysis of studies on can elicit elevated glucocorticoid levels trauma in CHR cohorts reveals that (Ruby et al., 2014). Given the interaction childhood adversity/ET has an estimated between glucocorticoid and dopaminergic 33% attributable risk for psychosis, even pathways, the mechanisms underlying this after controlling for potential confounds association may be that early experiences of such as genetic vulnerability, comorbidities, trauma increase glucocorticoid levels, drug use, ethnicity, urbanicity, and IQ subsequently leading to hyperactivity of (Varese et al., 2012). These data indicate a dopaminergic systems, and ultimately the clear relationship between traumatic events development of positive symptoms in in childhood and risk for psychosis. We adolescence and young adulthood. build on these findings by looking at associations of different types of trauma 1.2. Negative Symptoms with specific symptom profiles in CHR individuals. The literature is inconclusive in respect to the association of ET and negative 1.1. Positive Symptoms symptoms in CHR individuals. An early study showed no association of ET, defined The prevalence of ET is high in CHR broadly, with negative symptoms in a small individuals, and associated with the severity CHR cohort (Thompson et al., 2009). A of their positive symptoms (Thompson et al., later study in the same extended cohort 2009). Likewise, Kraan et al. (2015) however, showed that impaired stress reported a significant correlation between tolerance characterized CHR individuals,

Copyright © 2017, Archives of Psychology. All rights reserved. http://www.archivesofpsychology.org Redman S.L. et al. Archives of Psychology, vol. 1, issue 3, December 2017 Page 4 of 23 and was associated, over time, with both and/or exposure to war (Bonoldi et al., 2013; positive and negative symptom severity, as Matheson, Shepard, Pinchbeck, Laurens, & well as depression, anxiety, and poor Carr, 2013; Varese et al., 2012a). The functioning (Devylder et al., 2013). It has variability in definition of trauma in these been hypothesized that early trauma may assessments reflects an ongoing debate lead to increased sensitization to stress, and among investigators. Some argue that the subsequently, to both positive and negative definition of trauma should be restricted symptoms in vulnerable individuals (Ruby et only to catastrophic events, and that al., 2014). Negative symptoms may including other non-life-threatening paradoxically reduce exposure to concurrent experiences will create an excessive and stressful events by leading to social overgeneralized classification of trauma, withdrawal, as CHR youths endorse fewer leading to overestimate of prevalence recent life events than healthy peers, which (McNally, 2009). However, others contend may be similar to the avoidance that the defining features of a traumatic characteristic of post-traumatic stress event are negative valence, lack of disorder (PTSD) (Kraan et al. (2015). Of controllability, and suddenness (Carlson & interest, PTSD involves high rates of Dalenberg, 2000) and that perceived threat psychosis, with reported prevalence as high of injury or death is not a necessary as 75% for psychotic symptoms of condition for being traumatized (Shalev & hallucinations and delusions (Hamner, Ursano, 2003). The field of research on the Frueh, Ulmer, & Arana, 1999). Given the effects of early trauma on the onset and overlap between PTSD and psychosis, some prevalence of psychotic-like and associated researchers hypothesize that psychotic symptoms would benefit from a standardized episodes, often accompanied by stressful approach and assessment of trauma. experiences of confusion, fear, and potential hospitalization, may serve as traumatic 2.1. Definitions of Trauma experiences in and of themselves (Harrison & Fowler, 2004; Stampfer, 1990). Recall of While definitions of trauma vary, a recent such events in individuals with psychosis review by Gibson and colleagues (2016) may worsen negative symptoms, evoking highlights a few central systems of anxiety and depression and fostering classification used by trauma researchers: (1) avoidance behaviors. exposure, via several pathways, to an event of actual death, threats of death or injury, or actual or threatened sexual violence as 2. Variability in Trauma Assessment defined by criteria in the Diagnostic and th Despite different measures being used to Statistical Manual of Mental Disorders-5 assess trauma across studies, there is a clear edition (DSM-5) (American Psychological signal that early trauma is prevalent among Association, 2013); (2) experiences of CHR individuals, in whom it is related to physical, sexual, and/or emotional/psycho- positive symptom severity. Details of that logical abuse, neglect, or bullying (Gray, association are less clear, given the Litz, Hsu, & Lombardo, 2004; van Dam et discrepancies in definition and measurement al., 2012; Varese et al., 2012a); and (3) of trauma across studies. Some studies experiences of parental loss or separation, circumscribe their definition of trauma to natural disasters, serious accidents, interpersonal events classified by intent to imprisonment, being kidnapped or held harm (i.e. physical or sexual abuse), while hostage, more generally denoted as others also include childhood emotional adversities (Gray et al., 2004; Kessler, abuse, neglect, bullying, catastrophic events, Davis, & Kendler, 1997). Depending on

Copyright © 2017, Archives of Psychology. All rights reserved. http://www.archivesofpsychology.org Redman S.L. et al. Archives of Psychology, vol. 1, issue 3, December 2017 Page 5 of 23 which features are included in trauma Present and Lifetime (KSAD-PL), a semi- assessments, estimated prevalence will vary, structured diagnostic interview (Axelson, as may findings of association with Birmaher, Zelazny, Kaufman, & Gill, 2009), symptom severity, making it particularly and the Childhood Trauma and Abuse scale, difficult to compare studies or aggregate an adapted measure of self-report used for data from multiple studies, when different perceived discrimination by the North trauma assessments are used. This has been American Prodromal Longitudinal Study demonstrated in a recent study by Trauelsen (NAPLS) group (Addington et al., 2013). et al. (2015) that showed a decrease in Among these assessments, definitions of correlation of specific traumatic events with trauma vary, with some using specific symptoms in first-episode psychosis after classifications and others categorizing controlling for other types of traumatic trauma more broadly. Differing events, suggesting potential confounding; methodologies (e.g. structured interview vs. the authors argue that it may be useful to self-report) also contribute to variations in find a measure of overall trauma burden. results, with self-report methods yielding higher rates of endorsement (Bendall, 2.2. Measures of Trauma Jackson, Hulbery, & McGorry, 2007). In addition to variance in measures, it should One challenge in the categorization of be kept in mind that other potential sources trauma is the level of subjectivity involved of bias and variability arise due to the in assessing traumatic experiences. Whether retrospective nature of the recall of trauma an event is judged to be of a catastrophically that occurred years previously, with traumatic nature or as non-threatening, but potential recall bias and forgetting, adverse, there may be wide variability in especially among at-risk individuals with how the same event is experienced by cognitive deficits, and social desirability individuals in respect to its traumatic nature. bias. Self-report is among the most commonly used methods of collecting data on ET. Recently, Mayo and colleagues (2017) 3. Impacts of Trauma Type reviewed 24 studies, comprising 14 distinct 3.1. Sexual Abuse History samples that studied ET and its clinical correlates in CHR individuals. Among more Specific exposure to sexual abuse has been recent studies of ET in CHR, conducted by strongly correlated with greater positive six research groups, eight used the self- symptom severity in CHR cohorts, with report measure of the Childhood Trauma these positive symptoms reflecting greater Questionnaire (CTQ), a 28-item screen for incidence of sexual content (Thompson et five types of trauma including emotional, al., 2010). Remarkably, in a large CHR physical, and sexual abuse, and emotional cohort (n=416), sexual abuse in childhood and physical neglect (Bernstein & Fink, was a significant predictor of psychosis 1998). Other trauma assessments used in transition (Thompson et al., 2014). Across CHR studies include the Trauma History studies, the range of prevalence of sexual Screen (THS), a 14-item self-report measure abuse history is 22-31% in CHR individuals, designed for PTSD (Carlson et al., 2011), somewhat higher than the lifetime the Trauma and Distress Scale (TADS), a prevalence of 15-25% in the general European self-rating scale of childhood and population (Kraan et al., 2015; Falukozi & early adult traumatic experiences (Patterson Addington, 2012; Bechdolf et al., 2010; et al., 2002), the Kiddie Schedule for Russo et al., 2014; Thompson et al., 2016; Affective Disorders and Schizophrenia- Thompson et al., 2010; Thompson et al.,

2009). The increased prevalence of sexual 3.3. Emotional Abuse, Neglect & Bullying abuse history in CHR individuals, and its predictive power for psychosis onset, may Beyond sexual and physical abuse, reflect the development of altered awareness emotional abuse, neglect, and maltreatment and distorted interpretations of the external can also have significant negative effects on world, increasing risk for paranoia, mental health. There are high rates of perceptual abnormalities, and social reported emotional abuse (41.5-75%) and withdraw/avoidance, based on early neglect (59-100%) in CHR youths as experiences of mistrust and violation. compared to healthy controls (33%) (Thompson et al., 2009; Tikka et al., 2013). Further, emotional abuse and neglect among 3.2. Physical Abuse History CHR samples has been associated with Like sexual abuse, physical abuse is more greater Schneiderian first-rank symptoms prevalent in CHR individuals than in the and higher Schneiderian total scores (Sahin general population, including et al., 2013). A recent large CHR study of demographically-matched, healthy controls the NAPLS-2 cohort (n=764) showed that (Sahin et al., 2010; Stowkowy et al., 2013; CHR individuals report high perceived Stowkowy et al., 2016). An early study levels of trauma, discrimination, and reported that physical abuse was endorsed bullying, with discrimination serving as a by 83% of CHR individuals queried, and significant predictor of transition to was specifically associated with severity of psychosis (Stowkowy et al., 2016). These disorganization and suspiciousness among higher rates of reported emotional trauma CHR samples (Thompson et al., 2009). Later and bullying have been associated in the studies found an association of reported large NAPLS CHR consortium with childhood abuse with cognitive deficits in depression, anxiety, and poor self-esteem CHR individuals, which may mediate the (Addington et al., 2013), associations that association of early physical abuse with later exists more broadly beyond CHR, psychotic symptoms, as such deficits are specifically for bullying, and including common in CHR cohorts (Ucok et al., 2015; associations also with aggression and Yung et al., 2015). Early experiences of suicidality in addition to poor self-esteem, physical abuse may increase the use of threat depression, and positive symptoms appraisals in cognitive development, (Arseneault, Bowes, & Shakoor, 2010). predisposing individuals to the Specific to CHR youth, up to 60% of the misinterpretation of external stimuli, and the NAPLS cohort endorsed a lifetime history of expression of psychotic symptoms. physical or psychological bullying, Additional mechanisms potentially involved compared to 36% in healthy controls in the association between early physical (Addington et al., 2013). This experience of trauma and psychosis risk may include bullying, likely contributes to the poor social frequent, and/or increased hyperarousal of function that has been shown to be so the body‟s acute stress response to common among CHR youths (Carrion et al., threatening situations, which may indirectly 2013), and merits further research. The link influence the heightened stress sensitivity to between of emotional neglect and both life events and daily activities observed mistreatment with prodromal symptoms and in CHR samples (Trotman et al., 2014). social impairment may be explained by a failure of a child‟s environment to provide stimulating, positive support to the developing brain, leading to disruptions in cognitive functioning (Heins et al., 2011;

Copyright © 2017, Archives of Psychology. All rights reserved. http://www.archivesofpsychology.org Redman S.L. et al. Archives of Psychology, vol. 1, issue 3, December 2017 Page 7 of 23 van Dam, Korver-Nieberg, Velthorst, in the pathogenesis of psychosis (Dean & Meijer, & de Haan, 2014b). However, the Murray, 2005). causal direction of the association is not entirely clear, as individuals with an Beyond perinatal and delivery increased risk for developing psychosis may complications, a meta-analysis of have been more susceptible to bullying and population-based studies shows strong and maltreatment in general. significant associations between schizophrenia and complications in 3.4. Pre-and Perinatal Trauma pregnancy, including bleeding, preeclampsia, diabetes, and abnormal fetal Prenatal/perinatal trauma, specifically growth/development (low weight, congenital obstetric complications, are known risk deformities, small head circumference) factors for schizophrenia and related (Cannon, Jones, & Murray, 2002). Maternal psychotic disorders, such that it is not gestational infections, including influenza, surprising that there is a significantly herpes simplex, and rubella have been increased prevalence of obstetric clearly identified as risk factors for complications among CHR individuals psychosis in offspring (Brown & Susser, compared to controls (Fusar-Poli et al., 2002; Bulka et al., 2001), as have maternal 2017). Hypoxia-associated obstetric depression during pregnancy (Jones, complications have also been associated Rantakallio, Hartikainen, Isohanni, & Sipila, with an earlier risk of onset in schizophrenia 1998), unwanted pregnancy (Myhrman, (Rosso et al., 2000). After controlling for Rantakallio, Isohanni, Jones, & Partanen, prenatal infection and fetal growth 1996), and exposure to war and disasters retardation, fetal hypoxia remains (van Os & Selten, 1998; Funai, Paltiel, significantly more prevalent in early-onset Malaspina, Friedlander, Deutsch, & Harlap, schizophrenia, as compared with non- 2005). While the causal mechanisms remain psychiatric controls, unaffected siblings, and unclear, one theory suggests that a later-onset schizophrenia cases. A dose- reactivation of the initial infection causes an dependent association has also been found, inflammatory response in the developing with a linear relationship between the fetal brain that may facilitate the number of hypoxia-causing obstetric neuropathological effects related to an complications and earlier age of increased risk for psychosis (Miller, schizophrenia onset (Cannon et al., 2000). In Culpepper, Rapaport, & Buckley, 2013). a large schizophrenia cohort (n=854), Other forms of prenatal maternal stress individuals with illness onset prior to age 22 exposure may increase psychosis risk by were 2.7 times more likely to have a history increasing stress responsivity via of abnormal presentation at birth, and 10 modifications of the Hypothalamic-Pituitary- times more likely to have a history of Adrenal (HPA) axis in utero (Corcoran et al., Cesarean birth complications, as compared 2003). to individuals with later illness onset (Verdoux et al., 1997). The consistent 4. Clinical Implications of Studying correlation between fetal hypoxia/birth Trauma in CHR complications and psychosis onset, particularly early onset, suggests a Aside from the methodological issues with mechanism of neurotoxicity affecting brain defining and measuring trauma, the development, in the context of both genetic subjective and retrospective nature of trauma vulnerability and early environmental stress, assessment, in general, may prove difficult for this group of individuals. Several

Copyright © 2017, Archives of Psychology. All rights reserved. http://www.archivesofpsychology.org Redman S.L. et al. Archives of Psychology, vol. 1, issue 3, December 2017 Page 8 of 23 neurobiological impairments, genetic HPA hyperactivity may be a familial risk predispositions, and perceptual and factor for psychosis. Ruby et al. (2014) posit neurocognitive deficits that often present in that individuals with predisposition to stress prodromal patients may pose significant sensitivity may experience greater distress in conflict in accurately evaluating trauma in response to both traumatic events and other this population. childhood stressors relative to others with similar exposures. Thus, early life events 4.1. Stress sensitivity may be experienced as more traumatic, and interact with epigenetic pathways to modify Increased stress sensitivity has been gene expression and worsen stress identified as a potential causal factor in the sensitivity. As such, the activation of these expression of several psychiatric conditions, pathways in the stress cascade, prior to including psychosis. Individuals with a symptom onset, may worsen the effects of genetic vulnerability for psychosis also have ET in CHR individuals. dysregulation in their HPA axis and associated neurotransmitter systems (Ruby 4.2. Genetic Influences et al., 2014; Walker et al., 2011). Hyperactivity of the HPA axis is a replicated Socio-environmental and genetic factors are finding in CHR studies, as evidenced by known interdependent factors in the increased abnormalities in cortisol secretion, pathogenesis of psychosis (Van Winkel, and significantly higher mean diurnal Stefanis, & Myin-Germeys, 2008). For salivary cortisol levels compared to healthy example, in a study of the general individuals (Sugranyes et al., 2012; population, Alemany et al. (2011) found Chaumette et al., 2016; Walker et al., 2013). increased psychotic experiences in the Increased cortisol levels are positively context of early trauma exposure in carriers correlated with symptom severity in CHR of the MET allele for brain-derived persons (Walker et al., 2013), specifically neurotrophic factors (BDNF). BDNF serves suspiciousness, as well as impaired stress a vital role in several neurobiological tolerance and anxiety (Corcoran et al., regulatory systems including hippocampal 2012). Neuroimaging studies show neurogenesis, and dopaminergic and functional abnormalities in striatal dopamine GABAergic synthesis and functioning (Ray, synthesis and release in CHR samples, with Weickert, Wyatt, & Webster, 2011; Hyman some predictive power for psychosis onset & Hofer, 1991; Guillin, Diaz, Carroll, & (Bois, Whalley, McIntosh, & Lawrie, 2015; Griffon, 2001; Ruby et al., 2014). A Howes, McCutcheon, Owen, & Murray, functional gene variant, Val66Met, resulting 2017; Howes et al., 2011). Reductions of in the downregulation of BDNF, is linked to hippocampal volume, a brain structure with reduced hippocampal volume in human and a critical role in regulating the HPA axis, is animal models (Chen et al., 2006; Egan et also a replicated finding in psychosis and al., 2003), a common finding in CHR and CHR cohorts (Mondelli et al., 2011; Ruby et psychosis cohorts (Ruby et al., 2014). al., 2015, see Aiello et al., 2012 for review). Studies on this BDNF polymorphism in healthy populations show that met-BDNF Enhanced stress response to daily events and allele carriers have worse episodic memory activities has also been found in first-degree performance and reduced hippocampal relatives of CHR individuals and psychosis engagement during functional magnetic patients, compared with healthy controls resonance imaging (fMRI), as well as (Myin-Germeys, van Os, Schwartz, Stone, & bilateral reductions in hippocampal gray Delespaul, 2001; Aiello et al., 2012). Thus, matter, independent of age and gender

(Pezawas et al., 2004; Bueller et al., 2006; of gene-environment interactions (Veras et Egan et al., 2003; Hariri et al., 2003). al., 2017), including a higher sensitivity to Additionally, cultured hippocampal neurons trauma among met allele carriers, likely transfected with met-BDNF fail to explained by pathological stress-induced concentrate BDNF in secretory granules and changes in neural systems related to dendritic processes, and show decreased impaired BDNF functioning. Other studies depolarization-induced secretion (Egan et have also shown clinical effects of gene- al., 2003, Chen et al., 2006). Together with environment interactions, including animal data linking BDNF to the modulation psychosis (Peerbooms et al., 2012; for of essential neural processes in the review see Holtzman et al., 2013). hippocampus (Taliaz, Stall, Dar, & Zangen, Individuals with a genetic predisposition for 2009; Choi et al., 2010), these findings psychosis may experience greater amounts suggest that the genotypic expression of of stress and/or enhanced stress perception BDNF polymorphisms, specifically the based on gene-environment interactions. presence of the met-BDNF allele, elicits Given the high prevalence of met-BDNF changes in synaptic and cellular plasticity alleles in schizophrenia, CHR individuals via activity and context-dependent may also be at increased risk of carrying mechanisms that compromise both the BDNF polymorphisms, potentially development and function of the predisposing them to related impairments in hippocampus (Pezawas et al., 2004). With its hippocampal-dependent memory functions. strong association to hippocampal functions of learning and memory, several genetic 4.3. Altered Perceptions studies have investigated possible correlations between BDNF polymorphisms Several models of psychosis propose an and psychosis risk, showing significantly association between altered cognitive and increased risk of schizophrenia among met- perceptual mechanisms and the BDNF allele carriers compared to case- manifestation of symptoms. While trauma controls (Gratacos et al., 2007; Green, exposure may contribute to the genesis Matheson, Shepherd, Weickert, & Carr, and/or exacerbation of psychosis, preceding 2011). Implicated in several perceptual biases or disturbances may neurodevelopmental and neurodegenerative influence how trauma is experienced and disorders (Huntington‟s disease, Down‟s recalled in at-risk populations. Individuals at syndrome, Alzheimer‟s disease, CHR for psychosis endorse higher levels of schizophrenia) (Zuccato et al., 2001; subjective stress to both life events and daily Bimonte-Nelson, Hunter, Nelson, & stressors relative to healthy controls Granholm, 2003; Weickert et al., 2003, (Trotman et al., 2014). Perceived stress level Banquet, Gorski, & Jones, 2004), the altered is indicated as a mediator between ET and expression of BDNF may be a genetically attenuated positive psychotic symptoms driven factor in the reduction of (Gibson et al., 2014). Further evidence from development and plasticity of the a large systematic review of 170 hippocampus, interfering with the normal independent data sets presents high developmental maturation of many essential perceived levels of stress as prevalent in cognitive and behavioral functions. CHR cohorts (Fusar-Poli et al., 2017). Additionally, Millman et al. (2017) showed A genetic link between ET and a positive correlation between greater psychological symptoms has been shown in perceptions of social stress with symptom a group of met-BDNF carriers with severity in CHR individuals. Stronger schizophrenia, highlighting the importance associations between activity- related stress

Copyright © 2017, Archives of Psychology. All rights reserved. http://www.archivesofpsychology.org Redman S.L. et al. Archives of Psychology, vol. 1, issue 3, December 2017 Page 10 of 23 and psychotic symptoms are found in CHR an externalizing bias, such orientations patients, relative to those with threshold towards an external locus of control have psychosis (Steen et al., 2017), suggesting been shown to be a predictor of psychosis that stress sensitivity may drive positive (Frenkel et al., 1995). A large longitudinal symptom expression early in the course of study (n=6,455) showed that children who illness, but that symptoms may become more reported externalizing biases were at endogenous and independent of the significantly increased risk of developing environment later in illness course. psychotic symptoms by age 13 (Thompson et al., 2011). One study found that CHR 4.3.1. Information Processing individuals have increased concerns about locus of control, as compared with non-CHR Aberrant attribution of salience to irrelevant patient controls (Thompson et al., 2015), but stimuli has been hypothesized as core to a separate study found that CHR individuals psychotic symptoms (Kapur, 2003; Roiser, and healthy individuals had a similar Howes, Chaddock, Joyce & McGuire, 2012; external-personalizing attributional style van Winkel et al., 2013). Disproportional (Devylder et al., 2013). allocation of attention to threatening stimuli has been linked to inappropriate inferences 4.3.3. Negative Schemas and paranoid ideation (Sherrer, 2011). Behavioral and neurophysiological measures Many models of psychosis posit a of such information processing biases have relationship between negative schemata been shown in CHR individuals, as they about the self and vulnerability for psychosis have longer reaction times to threatening (Garety, Kuipers, Fowler, Freeman, & words on the Emotional Stroop Task Bebbington, 2001). Negative schemas have (Bendall et al., 2008; Roiser et al., 2013; shown to be a strong mediator in the Nieman et al., 2014). Increased sensitivity to relationship between ET and subclinical minor stressors and enhanced threat paranoia and the prediction of paranoia and anticipation characterize early course in hallucinations in CHR populations psychosis, as compared with healthy (Addington & Tran, 2009; Gracie et al., individuals (Reininghaus et al., 2016), with 2007). A recent study by Appiah-Kusi et al. an increased association of aberrant salience (2017) has shown that relative to healthy with psychotic experiences in CHR cohorts. controls, CHR individuals present with more There may be an initial attention bias negative schemas, and less positive schemas, towards threatening stimuli, which may about themselves and others, in addition to aggravate psychological and physiological increased reports of various types of experiences of trauma. childhood trauma exposures. The direction of such negative schemas remains unclear 4.3.2. Externalizing Bias and the possibility exists that these individuals start out with altered cognitive A common feature found in both psychosis scripts, which may in turn amplify early patients and CHR individuals is the experiences of trauma. interpretation of private events and experiences as having external implications, 4.3.4. Emotion Processing with an increased prevalence of believing that behavior may be controlled by forces Regulating and recognizing emotions, in outside themselves (Bentall & Fernyhough, oneself and in others, is an important and 2008; Frenkel, Kugelmass, Nathan, & adaptive skill necessary to thrive in our Ingraham, 1995). Commonly referred to as social world. Unfortunately, patients with

Copyright © 2017, Archives of Psychology. All rights reserved. http://www.archivesofpsychology.org Redman S.L. et al. Archives of Psychology, vol. 1, issue 3, December 2017 Page 11 of 23 psychotic disorders often struggle to attain converters and healthy controls (Corcoran et this skill and typically demonstrate profound al., 2015). and detrimental disturbances in emotion processing. Comprehensive evaluations of Current research reports a strong link emotion awareness, regulation, and social between dysfunctional emotion awareness functioning in schizophrenia patients, shows and poor social functioning in CHR a significantly reduced ability to describe individuals, showing such deficits, and identify their own emotions relative to particularly an inability to describe feelings, healthy controls (Kimhy et al. 2012). This predicted 23.2% of variance in social same study established further deficits in functioning (Kimhy et al., 2016). Taken emotion regulation among persons in the together, these findings add to the consistent schizophrenia group, who presented with characterization of limited emotional decreased use of effective emotion processing among at-risk, and psychotic regulation techniques (less reappraisal) and individuals, as well as underscore the increased use of ineffective emotion important role these emotional capacities regulation strategies like suppression. serve in one‟s abilities to socialize. As such, Similar findings have been replicated in current evidence offers robust indications for CHR cohorts, indicating significant emotion processing issues in CHR cohorts difficulties in verbalizing, identifying, and that may ultimately affect their interpretation analysis of their own emotions relative to of early experiences, as well as predispose controls and healthy siblings (Van der Velde them as victims of social trauma like et al., 2015). Dysfunctional emotion bullying, victimization, and emotional abuse. regulation in CHR cohorts includes reduced reports of actively using effective emotion 4.4. Neurocognitive Impairments regulation strategies, specifically reappraisal, Premorbid intellectual and neurocognitive in daily life relative to controls. impairments, including learning, memory, Neuroimaging data of the same CHR and executive functioning deficits, are subjects suggests mechanisms that underlie common in psychotic disorders (Fuller et al., emotional processing deficits, specifically 2002; Reichenberg et al., 2002; Hutton et al., decreased activation of the left ventrolateral 1998). Specific impairments in the visual prefrontal cortex, a brain region involved in reproduction and memory indexes of the reappraisal (Diekhof, Geier, Falkai, & Wechsler Memory Scale-Revised (WMS-R) Gruber, 2011), during fMRI reappraisal are found in CHR patients who transition to tasks (Van der Velde et al., 2015). Kimhy psychosis, relative to non-converters and and colleagues (2016) corroborate such healthy controls (Brewer et al., 2006). findings, illustrating extensive emotion Spatial working memory and assessment of awareness and regulation deficits, of short term memory are also significantly comparable severity, in both CHR and worse in CHR groups compared to controls schizophrenia groups relative to healthy (Wood et al., 2003; Smith, Park, & controls. Further investigations of impaired Cornblatt, 2006). Working memory deficits emotional processing in CHR populations are also observed in non-psychiatric relatives suggest a potentially predictive value of of patients with schizophrenia (Park, these deficits. One such study showed Holtzman, & Goldman-Rakic, 1995; Myles- significantly poorer performance in facial Worsley & Park, 2002; MacDonald, Pogue- emotion recognition among those CHR Geile, Johnson, & Carter, 2003), suggesting individuals who later transitioned to these cognitive deficits have a genetic schizophrenia, relative to both non- component. Correspondingly, in the large

NAPLS cohort, CHR individuals with a greater total and positive symptom severity, family history of psychosis have worse decreased overall functioning, decreased cognitive functioning (Woodberry et al., quality of life, and poorer response to 2010), which itself predicted transition to antipsychotic medications (Marshall et al., psychosis. Recent research shows an 2005; Perkins, Gu, Boteva, & Lieberman, association between aerobic fitness level and 2005). Moreover, longer DUP may have improved neuropsychological functioning, neurotoxic effects on the brain, resulting in and positive effects of aerobic exercise on gray matter volume reduction with symptom cognitive functioning in psychosis and at- progression and increased cognitive risk samples (Kimhy et al., 2015; Mittal et deterioration (Lieberman et al., 2001; al., 2013). Relative to a treatment as usual Amminger, Edwards, Brewer, Harrigan, & (TAU) intervention group, and their own McGorry, 2002). Neuroimaging studies baseline, schizophrenia patients assigned to show increased brain abnormalities in early an aerobic exercise treatment group onset schizophrenia cases, as progressive increased their overall aerobic fitness, patterns of gray matter loss in several brain improved dramatically on neurocognitive regions correlate with both psychotic assessments, and showed elevated BDNF symptom severity and increased neuromotor, serum levels (Kimhy et al., 2015). Similar perceptual, and frontal executive deficits studies in CHR cohorts demonstrate observed in disease advancement significant correlations between high levels (Thompson et al., 2001). Additionally, of inactivity and decreased occupational retrospective accounts of schizophrenia functioning in at-risk individuals relative to cases prior to first hospitalization show healthy controls (Mittal et al., 2013). Such increased rates of premorbid functional data reflects a probable relationship between deficiencies resulting in various social, physical activity and neuropsychological economic, professional, academic, and functioning in psychosis, implicating a interpersonal losses (Hafner, Nowotny, sedentary lifestyle in the potential Loffler, van der Heiden, & Maurer, 1995). development and/or exacerbation of Given the critical developmental time period neurocognitive deficits observed in these in which psychosis typically presents, populations. These findings, in addition to patients with longer DUP are at higher risk neuroimaging data documenting aberrations of experiencing detrimental, and possibly in frontal and medial temporal lobes in irreversible, outcomes that may negatively relation to executive functioning, episodic affect quality of life and inhibit opportunities and working memory in schizophrenia in the future. With so much at stake, patients, further support the interaction evaluating risk factors to enhance detection between environmental exposures and methods of at-risk populations, should genetic liability in psychosis development continue to be prioritized in future research. (Reichenberg & Harvey, 2007). As reviewed, documentation of ET may be a useful tool in understanding potential Conclusion mechanisms of psychosis development and The accumulation of comprehensive and remains a research topic of interest in CHR consistent research on the initial prodromal cohorts. While there is a clear association of phase of psychosis underscores the ET and symptom severity in CHR cohorts, importance of both early identification and nonetheless the field would benefit from intervention in CHR populations. Longer standardization of trauma assessments duration of untreated psychosis (DUP) is employed. A comprehensive meta-analysis related to worse general outcomes, including examining the association between

Copyright © 2017, Archives of Psychology. All rights reserved. http://www.archivesofpsychology.org Redman S.L. et al. Archives of Psychology, vol. 1, issue 3, December 2017 Page 13 of 23 childhood adversity/trauma and psychosis References risk, including a large assortment of case- controlled, prospective and quasi- Abuse, S. (2014). Mental Health Services prospective, population-based and cross- Administration, Trauma-informed care in sectional studies, reports that all types of behavioral health services. Treatment early trauma, regardless of the precise nature improvement protocol (TIP) series, 57. of exposure, are related to an increased risk Addington, J., & Tran, L. (2009). Using the of psychosis (Varese et al., 2012a). brief core schema scales with individuals at However, standardization of measures used clinical high risk of psychosis. Behavioural would allow for a better understanding of the and Cognitive Psychotherapy, 37(02), 227– role of trauma types and their effects on 231. specific symptoms, and a better estimate of prevalence. The use of self-administered, Aiello, G., Horowitz, M., Hepgul, N., subjective report measures and semi- Pariante, C. M., & Mondelli, V. (2012). structured clinical interviews, in Stress abnormalities in individuals at risk for conjunction, is recommended as the most psychosis: a review of studies in subjects effective method of assessing trauma. While with familial risk or with “at risk” mental the initial self-administrated trauma state. Psychoneuroendocrinology, 37(10), inventories will promote a sense of safety 1600-1613. and honest disclosure by reducing shame, guilt, and fear of judgment, a follow-up Alemany, S., Arias, B., Aguilera, M., Villa, clinical interview by trained screeners H., Moya, J., Ibáñez, M. I., ... & Fañanás, L. ensures the subject adequately understands (2011). Childhood abuse, the BDNF- the content and process of the assessment to Val66Met polymorphism and adult enhance clarification and accuracy of results psychotic-like experiences. The British (Abuse, 2014). We would advocate the use Journal of Psychiatry, 199(1), 38-42. of The Early Trauma Inventory (ETI), which Amminger, G. P., Edwards, J., Brewer, W. was employed in the early study by J., Harrigan, S., & McGorry, P. D. (2002). Thompson et al., (2009). It is a well- Duration of untreated psychosis and validated and reliable trauma assessment cognitive deterioration in first-episode with demonstrated inter-rater reliability, test- schizophrenia. Schizophrenia research, retest reliability, internal consistency and 54(3), 223-230. validity (Bremner, Vermetten, & Mazure, 2000). With adapted versions for clinical American Psychiatric Association (APA). interviews and self-administered measures, (2000). Diagnostic and statistical manual of the ETI consists of 56 items reflecting mental disorders: DSM-IV-TR. Washington, physical, emotion, and sexual abuse, as well DC: American Psychiatric Association. as general traumatic experiences, and shows good convergent validity relative to other American Psychiatric Association (APA). trauma instruments. Given the heterogeneity (2013). Diagnostic and statistical manual of of symptoms, early life experiences, and mental disorders: DSM-5 (5th ed.). various biological vulnerabilities among Arlington, VA: American Psychiatric CHR populations, such an extensive, yet Publishing, Inc. easily standardized measure of trauma, is a Appiah-Kusi, E., Fisher, H. L., Petros, N., unique, yet essential tool in the study of such Wilson, R., Mondelli, V., Garety, P. A., ... & complex relationships. Bhattacharyya, S. (2017). Do cognitive schema mediate the association between

Copyright © 2017, Archives of Psychology. All rights reserved. http://www.archivesofpsychology.org Redman S.L. et al. Archives of Psychology, vol. 1, issue 3, December 2017 Page 14 of 23 childhood trauma and being at ultra-high and psychotic disorders: a systematic, risk for psychosis?. Journal of psychiatric critical review of the evidence. research, 88, 89-96. Schizophrenia bulletin, 34(3), 568-579. Arseneault, L., Bowes, L., & Shakoor, S. Bentall, R. P., & Fernyhough, C. (2008). (2010). Bullying victimization in youths and Social predictors of psychotic experiences: mental health problems:„Much ado about Specificity and psychological mechanisms. nothing‟?. Psychological medicine, 40(5), Schizophrenia Bulletin, 34(6), 1012–1020. 717-729. Bernstein, D. P., & Fink, L. Arseneault, L., Cannon, M., Fisher, H. L., (1998). Childhood trauma questionnaire: A Polanczyk, G., Moffitt, T. E., & Caspi, A. retrospective self-report: Manual. (2011). Childhood trauma and children's Psychological Corporation. emerging psychotic symptoms: a genetically sensitive longitudinal cohort study. Bimonte-Nelson, H. A., Hunter, C. L., American Journal of Psychiatry, 168(1), 65- Nelson, M. E., & Granholm, A. C. E. (2003). 72. Frontal cortex BDNF levels correlate with working memory in an animal model of Ashcroft, K., Kingdon, D. G., & Chadwick, Down syndrome. Behavioural brain P. (2012). Persecutory delusions and research, 139(1), 47-57. childhood emotional abuse in people with a diagnosis of schizophrenia. Psychosis, 4(2), Bois C, Whalley H, McIntosh A, Lawrie S. 168-171. (2015), Structural magnetic resonance imaging markers of susceptibility and Axelson, D., Birmaher, B., Zelazny, J., transition to schizophrenia: a review of Kaufman, J., & Gill, M. K. (2009). The familial and clinical high risk population Schedule for Affective Disorders and studies. J Psychopharmacol 29(2):144–54. Schizophrenia-Present and Lifetime Version doi:10.1177/0269881114541015 (K-SADS-PL) 2009 Working Draft. Advanced Centre for Intervention and Bonoldi, I., Simeone, E., Rocchetti, M., Services Research, Western Psychiatric Codjoe, L., Rossi, G., Gambi, F., ... & Fusar- Institute and Clinics. Poli, P. (2013). Prevalence of self-reported childhood abuse in psychosis: a meta- Baquet ZC, Gorski JA, Jones KR (2004) analysis of retrospective studies. Psychiatry Early striatal dendrite deficits followed by research, 210(1), 8-15. neuron loss with advanced age in the absence of anterograde cortical brain- Bremner, J. D., Vermetten, E., & Mazure, C. derived neurotrophic factor. J M. (2000). Development and preliminary Neurosci 24: 4250-4258 psychometric properties of an instrument for the measurement of childhood trauma: the Bechdolf A, Thompson A, Nelson B, Cotton Early Trauma Inventory. Depression and S, Simmons MB, Amminger GP, et al. anxiety, 12(1), 1-12. Experience of trauma and conversion to psychosis in an ultra- high-risk (prodromal) Brewer, W. J., Wood, S. J., Phillips, L. J., group. Acta Psychiatr Scand (2010) Francey, S. M., Pantelis, C., Yung, A. R., ... 121(5):377–84. doi:10.1111/j.1600- & McGorry, P. D. (2006). Generalized and 0447.2010.01542.x specific cognitive performance in clinical high-risk cohorts: a review highlighting Bendall, S., Jackson, H. J., Hulbert, C. A., & potential vulnerability markers for McGorry, P. D. (2007). Childhood trauma psychosis. Schizophrenia bulletin, 32(3),

538-555. of functional outcome in individuals at clinical high risk for psychosis. JAMA Brown, A. S., & Susser, E. S. (2002). In psychiatry, 70(11), 1133-1142. utero infection and adult schizophrenia. Developmental Disabilities Research Chen, Z. Y., Jing, D., Bath, K. G., Ieraci, A., Reviews, 8(1), 51-57. Khan, T., Siao, C. J., ... & Hempstead, B. L. (2006). Genetic variant BDNF (Val66Met) Bueller, J. A., Aftab, M., Sen, S., Gomez- polymorphism alters anxiety-related Hassan, D., Burmeister, M., & Zubieta, J. K. behavior. Science, 314(5796), 140-143. (2006). BDNF Val66Met allele is associated with reduced hippocampal volume in healthy Chaumette B, Kebir O, Mam-Lam-Fook C, subjects. Biological psychiatry, 59(9), 812- Morvan Y, Bourgin J, Godsil BP, et al. 815. (2016). Salivary cortisol in early psychosis: new findings and meta-analysis. Buka, S. L., Tsuang, M. T., Torrey, E. F., Psychoneuroendocrinology 63:262–70. Klebanoff, M. A., Bernstein, D., & Yolken, doi:10.1016/j. psyneuen.2015.10.007 R. H. (2001). Maternal infections and subsequent psychosis among offspring. Choi, D. C., Maguschak, K. A., Ye, K., Archives of general psychiatry, 58(11), Jang, S. W., Myers, K. M., & Ressler, K. J. 1032-1037. (2010). Prelimbic cortical BDNF is required for memory of learned fear but not Cannon, M., Jones, P. B., & Murray, R. M. extinction or innate fear. Proceedings of the (2002). Obstetric complications and National Academy of Sciences, 107(6), schizophrenia: historical and meta-analytic 2675-2680. review. American Journal of Psychiatry, 159(7), 1080-1092. Corcoran, C. M., Keilp, J. G., Kayser, J., Klim, C., Butler, P. D., Bruder, G. E., ... & Cannon, T. D., Rosso, I. M., Hollister, J. M., Javitt, D. C. (2015). Emotion recognition Bearden, C. E., Sanchez, L. E., & Hadley, T. deficits as predictors of transition in (2000). A prospective cohort study of individuals at clinical high risk for genetic and perinatal influences in the schizophrenia: a neurodevelopmental etiology of schizophrenia. Schizophrenia perspective. Psychological medicine, 45(14), Bulletin, 26(2), 351-366. 2959-2973. Carlson, E. B., & Dalenberg, C. J. (2000). A Corcoran, C. M., Smith, C., McLaughlin, D., conceptual framework for the impact of Auther, A., Malaspina, D., & Cornblatt, B. traumatic experiences. Trauma, Violence, & (2012). HPA axis function and symptoms in Abuse, 1(1), 4-28. adolescents at clinical high risk for Carlson, E.B., Smith, S.R., Palmieri, P.A., schizophrenia. Schizophrenia Dalenberg, C.J., Ruzek, J.I., Kimerling, R., research, 135(1), 170-174. Burling, T.A., & Spain, D.A. Corcoran, C., Walker, E., Huot, R., Mittal, (2011). Development and validation of a V., Tessner, K., Kestler, L., & Malaspina, D. brief self-report measure of trauma (2003). The stress cascade and exposure: The Trauma History Screen schizophrenia: etiology and onset. (PDF). Psychological Assessment, 23, 463- Schizophrenia bulletin, 29(4), 671-692. 477. doi: 10.1037/a0022294 Dean, K., & Murray, R. M. (2005). Carrión, R. E., McLaughlin, D., Goldberg, Environmental risk factors for psychosis. T. E., Auther, A. M., Olsen, R. H., Olvet, D. Dialogues in clinical neuroscience, 7(1), 69. M., ... & Cornblatt, B. A. (2013). Prediction

DeVylder, J. E., Ben‐David, S., Kimhy, D., nulliparous and parous women: the & Corcoran, C. M. (2013). Attributional Jerusalem Perinatal Study. Paediatric and style among youth at clinical risk for perinatal epidemiology, 19(1), 59-68. psychosis. Early intervention in psychiatry, 7(1), 84-88. Fusar-Poli, P., Bechdolf, A., Taylor, M. J., Bonoldi, I., Carpenter, W. T., Yung, A. R., Devylder, J. E., Ben-David, S., Schobel, S. & McGuire, P. (2012). At risk for A., Kimhy, D., Malaspina, D., & Corcoran, schizophrenic or affective psychoses? A C. M. (2013). Temporal association of stress meta-analysis of DSM/ICD diagnostic sensitivity and symptoms in individuals at outcomes in individuals at high clinical clinical high risk for psychosis. risk. Schizophrenia bulletin, 39(4), 923-932. Psychological medicine, 43(2), 259-268. Fusar‐Poli, P., Cappucciati, M., Rutigliano, Diekhof, E. K., Geier, K., Falkai, P., & G., Schultze‐Lutter, F., Bonoldi, I., Gruber, O. (2011). Fear is only as deep as Borgwardt, S., ... & McGlashan, T. H. the mind allows: a coordinate-based meta- (2015). At risk or not at risk? A analysis of neuroimaging studies on the meta‐analysis of the prognostic accuracy of regulation of negative affect. Neuroimage, psychometric interviews for psychosis 58(1), 275-285. prediction. World Psychiatry, 14(3), 322- 332. Egan, M. F., Kojima, M., Callicott, J. H., Goldberg, T. E., Kolachana, B. S., Bertolino, Fusar-Poli, P., Tantardini, M., De Simone, A., ... & Lu, B. (2003). The BDNF val66met S., Ramella-Cravaro, V., Oliver, D., polymorphism affects activity-dependent Kingdon, J., ... & Galderisi, S. (2017). secretion of BDNF and human memory and Deconstructing vulnerability for psychosis: hippocampal function. Cell, 112(2), 257- Meta-analysis of environmental risk factors 269. for psychosis in subjects at ultra high- risk. European Psychiatry, 40, 65-75. Falukozi, E., & Addington, J. (2012). Impact of trauma on attenuated psychotic Garety, P. A., Kuipers, E., Fowler, D., symptoms. Psychosis, 4(3), 203-212. Freeman, D., & Bebbington, P. E. (2001). A cognitive model of the positive symptoms of Frenkel, E., Kugelmass, S., Nathan, M., & psychosis. Psychological Medicine, 31(02), Ingraham, L. J. (1995). Locus of control and 189–195. mental health in adolescence and adulthood. Schizophrenia Bulletin, 21(2), Gibson, L. E., Anglin, D. M., Klugman, J. 219–226. T., Reeves, L. E., Fineberg, A. M., Maxwell, S. D., ... & Ellman, L. M. (2014). Stress Fuller, R., Nopoulos, P., Arndt, S., O‟Leary, sensitivity mediates the relationship between D., Ho, B. C., & Andreasen, N. C. (2002). traumatic life events and attenuated positive Longitudinal assessment of premorbid psychotic symptoms differentially by gender cognitive functioning in patients with in a college population sample. Journal of schizophrenia through examination of psychiatric research, 53, 111-118. standardized scholastic test performance. American Journal of Psychiatry, 159(7), Gracie, A., Freeman, D., Green, S., Garety, 1183-1189. P. A., Kuipers, E., Hardy, A., ... Fowler, D. (2007). The association between traumatic Funai, E. F., Paltiel, O. B., Malaspina, D., experience, paranoia and hallucinations: A Friedlander, Y., Deutsch, L., & Harlap, S. test of the predictions of psychological (2005). Risk factors for pre‐eclampsia in

Copyright © 2017, Archives of Psychology. All rights reserved. http://www.archivesofpsychology.org Redman S.L. et al. Archives of Psychology, vol. 1, issue 3, December 2017 Page 17 of 23 models. Acta Psychiatrica Scandinavica, Harrison, C.L., Fowler, D. (2004). Negative 116(4), 280–289. symptoms, trauma, and autobiographical memory: an investigation of individuals Gratacòs, M., González, J. R., Mercader, J. recovering from psychosis. J Nerv Ment Dis. M., de Cid, R., Urretavizcaya, M., & 192:745– 753. Estivill, X. (2007). Brain-derived neurotrophic factor Val66Met and Heins, M., Simons, C., Lataster, T., Pfeifer, psychiatric disorders: meta-analysis of case- S., Versmissen, D., Lardinois, M., ... Myin- control studies confirm association to Germeys, I. (2011). Childhood trauma and substance-related disorders, eating disorders, psychosis: A case–control and case- sibling and schizophrenia. Biological psychiatry, comparison across different levels of genetic 61(7), 911-922. liability, psychopathology, and type of trauma. American Journal of Psychiatry, Gray, M. J., Litz, B. T., Hsu, J. L., & 168(12), 1286–1294. Lombardo, T. W. (2004). Psychometric properties of the life events checklist. Holtzman, C. W., Trotman, H. D., Goulding, Assessment, 11(4), 330–341. S. M., Ryan, A. T., Macdonald, A. N., Shapiro, D. I., ... & Walker, E. F. (2013). Green, M. J., Matheson, S. L., Shepherd, A., Stress and neurodevelopmental processes in Weickert, C. S., & Carr, V. J. (2011). Brain- the emergence of psychosis. Neuroscience, derived neurotrophic factor levels in 249, 172-191. schizophrenia: a systematic review with meta-analysis. Molecular psychiatry, 16(9), Howes, O.D., Bose, S.K., Turkheimer, F., 960. Valli, I., Egerton, A., Valmaggia, L.R, et al. (2011). Dopamine synthesis capacity before Guillin, O., Diaz, J., Carroll, P., & Griffon, onset of psychosis: a prospective [18F]- N. (2001). BDNF controls dopamine D3 DOPA PET imaging study. Am J Psychiatry receptor expression and triggers behavioural 168(12):1311–7. doi:10.1176/appi.ajp.2011. sensitization. Nature, 411(6833), 86. 11010160 Häfner, H., Nowotny, B., Löffler, W., an der Howes, O.D., McCutcheon, R., Owen, M.J., Heiden, W., & Maurer, K. (1995). When and Murray, R.M. (2017). The role of genes, how does schizophrenia produce social stress, and dopamine in the development of deficits?. European archives of psychiatry schizophrenia. Biol Psychiatry 81(1):9–20. and clinical neuroscience, 246(1), 17-28. doi:10.1016/j.biopsych.2016.07.014 Hamner, M. B., Frueh, B. C., Ulmer, H. G., Hutton, S.B., Puri, B.K., Duncan, L.J., & Arana, G. W. (1999). Psychotic features Robbins, T.W., Barnes, T.R., Joyce, E.M. and illness severity in combat veterans with (1998). Executive function in first-episode chronic posttraumatic stress disorder. schizophrenia, Psychol Med. vol. 28 (pg. Biological Psychiatry, 45(7), 846-852. 463-473) Hariri, A. R., Goldberg, T. E., Mattay, V. S., Hyman, C., & Hofer, M. (1991). BDNF is a Kolachana, B. S., Callicott, J. H., Egan, M. neurotrophic factor for dopaminergic F., & Weinberger, D. R. (2003). Brain- neurons of the substantia nigra. Nature, derived neurotrophic factor val66met 350(6315), 230. polymorphism affects human memory- related hippocampal activity and predicts Janssen, I., Krabbendam, L., Bak, M., memory performance. Journal of Hanssen, M., Vollebergh, W., de Graaf, R. Neuroscience, 23(17), 6690-6694. and van Os, J. (2004), Childhood abuse as a

Copyright © 2017, Archives of Psychology. All rights reserved. http://www.archivesofpsychology.org Redman S.L. et al. Archives of Psychology, vol. 1, issue 3, December 2017 Page 18 of 23 risk factor for psychotic experiences. Acta recent life events in individuals at ultra high Psychiatrica Scandinavica, 109: 38–45. risk for psychosis: review and meta- doi:10.1046/j.0001-690X.2003.00217.x analysis. Schizophrenia research, 161(2), 143-149. Jones, P. B., Rantakallio, P., Hartikainen, A. L., Isohanni, M., & Sipila, P. (1998). Lieberman, J. A., Perkins, D., Belger, A., Schizophrenia as a long-term outcome of Chakos, M., Jarskog, F., Boteva, K., & pregnancy, delivery, and perinatal Gilmore, J. (2001). The early stages of complications: a 28-year follow-up of the schizophrenia: speculations on pathogenesis, 1966 north Finland general population birth pathophysiology, and therapeutic cohort. American Journal of Psychiatry, approaches. Biological psychiatry, 50(11), 155(3), 355-364. 884-897. Kapur, S. (2003). Psychosis as a state of MacDonald, A. W., Pogue-Geile, M. F., aberrant salience: a framework linking Johnson, M. K., & Carter, C. S. (2003). A biology, phenomenology, and pharmacology specific deficit in context processing in the in schizophrenia. American journal of unaffected siblings of patients with Psychiatry, 160(1), 13-23. schizophrenia. Archives of General Psychiatry, 60(1), 57-65. Kessler, R. C., Davis, C. G., & Kendler, K. S. (1997). Childhood adversity and adult Marshall, M., Lewis, S., Lockwood, A., psychiatric disorder in the US National Drake, R., Jones, P., & Croudace, T. (2005). Comorbidity Survey. Psychological Association between duration of untreated Medicine, 27(05), 1101–1119. psychosis and outcome in cohorts of first- episode patients: a systematic Kimhy, D., Vakhrusheva, J., Bartels, M. N., review. Archives of general psychiatry, Armstrong, H. F., Ballon, J. S., Khan, S., ... 62(9), 975-983. & Castrén, E. (2015). The impact of aerobic exercise on brain-derived neurotrophic Matheson, S. L., Shepherd, A. M., factor and neurocognition in individuals with Pinchbeck, R. M., Laurens, K. R., & Carr, schizophrenia: a single-blind, randomized V. J. (2013). Childhood adversity in clinical trial. Schizophrenia bulletin, 41(4), schizophrenia: a systematic meta- 859-868. analysis. Psychological medicine, 43(2), 225-238. Kimhy, D., Vakhrusheva, J., Jobson-Ahmed, L., Tarrier, N., Malaspina, D., & Gross, J. J. Mayo, D., Corey, S., Kelly, L. H., (2012). Emotion awareness and regulation in Yohannes, S., Youngquist, A. L., Stuart, B. individuals with schizophrenia: implications K., ... & Loewy, R. L. (2017). The role of for social functioning. Psychiatry research, trauma and stressful life events among 200(2), 193-201. individuals at clinical high risk for psychosis: a review. Frontiers in psychiatry, Kline, E., Millman, Z.B., Denenny, D., 8. Wilson, C., Thompson, E., Demro, C et al. (2016). Trauma and psychosis symptoms in McGorry, P. D., Yung, A. R., & Phillips, L. a sample of help-seeking youth. J. (2003). The “close-in” or ultra high-risk Schizophrenia Research. 175(1–3):174–9. model: a safe and effective strategy for doi:10.1016/j.schres.2016.04.006 research and clinical intervention in prepsychotic mental disorder. Schizophrenia Kraan, T., Velthorst, E., Smit, F., de Haan, bulletin, 29(4), 771-790. L., & van der Gaag, M. (2015). Trauma and

McNally, R. J. (2009). Can we fix PTSD in Stratification of risk estimation with DSM‐V?. Depression and anxiety, 26(7), information- processing and premorbid 597-600. functioning variables. Schizophrenia Bulletin, 40(6), 1482–1490. Miller, B. J., Culpepper, N., Rapaport, M. H., & Buckley, P. (2013). Prenatal Numata, S., Ueno, S. I., Iga, J. I., Yamauchi, inflammation and neurodevelopment in K., Hongwei, S., Ohta, K., ... & Kameoka, schizophrenia: a review of human N. (2006). Brain-derived neurotrophic factor studies. Progress in Neuro-Psychopharma- (BDNF) Val66Met polymorphism in cology and Biological Psychiatry, 42, 92- schizophrenia is associated with age at onset 100. and symptoms. Neuroscience letters, 401(1), 1-5. Millman, Z. B., Pitts, S. C., Thompson, E., Kline, E. R., Demro, C., Weintraub, M. J., ... Oswald, L.M., Wand, G.S., Kuwabara, H., & Schiffman, J. (2017). Perceived social Wong, D.F., Zhu. S., Brasic, J.R. (2014). stress and symptom severity among help- History of childhood adversity is positively seeking adolescents with versus without associated with ventral striatal dopamine clinical high-risk for psychosis. responses to amphetamine. Schizophrenia Research. Psychopharmacology. 231(12):2417–33. doi:10.1007/s00213-013-3407-z Mittal, V. A., Gupta, T., Orr, J. M., Pelletier- Baldelli, A., Dean, D. J., Lunsford-Avery, J. Park, S., Holzman, P. S., & Goldman-Rakic, R., . . . Millman, Z. B. (2013). Physical P. S. (1995). Spatial working memory activity level and medial temporal health in deficits in the relatives of schizophrenic youth at ultra high-risk for patients. Archives of General Psychiatry, psychosis. Journal of Abnormal Psychology, 52(10), 821-828. 122(4), 1101-1110. Patterson P., Skeate A., Birchwood M, et Myhrman, A., Rantakallio, P., Isohanni, M., al. (2002). TADS-EPOS 1.2. Birmingham: Jones, P., & Partanen, U. (1996). University of Birmingham. Unwantedness of a pregnancy and schizophrenia in the child. The British Peerbooms, O., Rutten, B. P. F., Collip, D., Journal of Psychiatry, 169(5), 637-640. Lardinois, M., Lataster, T., Thewissen, V., ... & Myin‐Germeys, I. (2012). Evidence that Myin-Germeys, I., van Os, J., Schwartz, J. interactive effects of COMT and MTHFR E., Stone, A. A., & Delespaul, P. A. (2001). moderate psychotic response to Emotional reactivity to daily life stress in environmental stress. Acta psychiatrica psychosis. Archives of general psychiatry, Scandinavica, 125(3), 247-256. 58(12), 1137-1144. Perkins, D. O., Gu, H., Boteva, K., & Myles‐Worsley, M., & Park, S. (2002). Lieberman, J. A. (2005). Relationship Spatial working memory deficits in between duration of untreated psychosis and schizophrenia patients and their first degree outcome in first-episode schizophrenia: a relatives from Palau, Micronesia. American critical review and meta-analysis. American Journal of Medical Genetics Part A, 114(6), Journal of Psychiatry, 162(10), 1785-1804. 609-615. Pezawas, L., Verchinski, B. A., Mattay, V. Nieman, D. H., Ruhrmann, S., Dragt, S., S., Callicott, J. H., Kolachana, B. S., Straub, Soen, F., van Tricht, M. J., Koelman, J. H., R. E., ... & Weinberger, D. R. (2004). The ... de Haan, L. (2014). Psychosis prediction: brain-derived neurotrophic factor val66met

Copyright © 2017, Archives of Psychology. All rights reserved. http://www.archivesofpsychology.org Redman S.L. et al. Archives of Psychology, vol. 1, issue 3, December 2017 Page 20 of 23 polymorphism and variation in human Ross, C., Anderson, G., Clark, P. (1994). cortical morphology. Journal of Childhood abuse and positive symptoms of Neuroscience, 24(45), 10099-10102. schizophrenia. Hospital & Community Psychiatry. 45:489–491. Ray, M. T., Weickert, C. S., Wyatt, E., & Webster, M. J. (2011). Decreased BDNF, Ruby, E., Polito, S., McMahon, K., trkB-TK+ and GAD67 mRNA expression in Gorovitz, M., Corcoran, C., & Malaspina, D. the hippocampus of individuals with (2014). Pathways associating childhood schizophrenia and mood disorders. Journal trauma to the neurobiology of of psychiatry & neuroscience: JPN, 36(3), schizophrenia. Frontiers in psychological 195. and behavioral science, 3(1), 1. Read, J., Os, J. V., Morrison, A. P., & Ross, Ruby, E., Rothman, K., Corcoran, C., Goetz, C. A. (2005). Childhood trauma, psychosis R. R., & Malaspina, D. (2015). Influence of and schizophrenia: a literature review with early trauma on features of schizophrenia. theoretical and clinical implications. Acta Early intervention in psychiatry. Psychiatrica Scandinavica, 112(5), 330-350. Russo, D.A., Stochl, J., Painter, M., Dobler, Reininghaus, U., Kempton, M. J., V., Jackson, E., Jones, P.B., et al. (2014). Valmaggia, L., Craig, T. K., Garety, P., Trauma history characteristics associated Onyejiaka, A., ... & Dazzan, P. (2016). with mental states at clinical high risk for Stress sensitivity, aberrant salience, and psychosis. Psychiatry Research. 220(1– threat anticipation in early psychosis: an 2):237–44. doi:10.1016/j.psychres. experience sampling study. Schizophrenia 2014.08.028 bulletin, 42(3), 712-722. Sahin, S., Yuksel, C., Guler, J., Karadayi, Reichenberg, A., & Harvey, P. D. (2007). G., Akturan, E., Gode, E., et al. (2013). The Neuropsychological impairments in history of childhood trauma among schizophrenia: Integration of performance- individuals with ultra high risk for psychosis based and brain imaging findings. is as common as among patients with first- Psychological bulletin, 133(5), 833. episode schizophrenia. Early Interv Psychiatry 7(4):414–20. Reichenberg, A., Weiser, M., Rabinowitz, J., doi:10.1111/eip.12022 Caspi, A., Schmeidler, J., Mark, M., ... & Davidson, M. (2002). A population-based Seidman, L. J., Giuliano, A. J., Meyer, E. C., cohort study of premorbid intellectual, Addington, J., Cadenhead, K. S., Cannon, T. language, and behavioral functioning in D., ... & Woods, S. W. (2010). patients with schizophrenia, schizoaffective Neuropsychology of the prodrome to disorder, and nonpsychotic bipolar psychosis in the NAPLS consortium: disorder. American Journal of Psychiatry, relationship to family history and conversion 159(12), 2027-2035. to psychosis. Archives of general Roiser, J. P., Howes, O. D., Chaddock, C. psychiatry, 67(6), 578-588. A., Joyce, E. M., & McGuire, P. (2012). Shalev, A. Y., & Ursano, R. J. (2003). Neural and behavioral correlates of aberrant Mapping the multidimensional picture of salience in individuals at risk for acute responses to traumatic stress. psychosis. Schizophrenia bulletin, 39(6), Reconstructing early intervention after 1328-1336. trauma, 118, 129.

Sherrer, M. V. (2011). The role of cognitive symptoms, and medication exposure in appraisal in adaptation to traumatic stress in youths at clinical high risk for adults with serious mental illness: A critical psychosis. Journal of psychiatric research, review. Trauma, Violence, & Abuse, 12(3), 46(11), 1389-1393. 151-167. Taliaz, D., Stall, N., Dar, D. E., & Zangen, Smith, C. W., Park, S., & Cornblatt, B. A. (2009). Knockdown of brain-derived (2006). Spatial working memory deficits in neurotrophic factor in specific brain sites adolescents at clinical high risk for precipitates behaviors associated with schizophrenia. Schizophrenia depression and reduces research, 81(2), 211-215. neurogenesis. Molecular psychiatry, 15(1), 80. Spauwen, J., Krabbendam, L., Lieb, R., Wittchen, H. U., & van Os, J. (2006). Impact Thompson, J. L., Kelly, M., Kimhy, D., of psychological trauma on the development Harkavy-Friedman, J. M., Khan, S., of psychotic symptoms: relationship with Messinger, J. W., ... & Corcoran, C. (2009). psychosis proneness. The British Journal of Childhood trauma and prodromal symptoms Psychiatry, 188(6), 527-533. among individuals at clinical high risk for psychosis. Schizophrenia research, 108(1), Stampfer, H.G. (1990). Negative 176-181. symptoms‟: a cumulative trauma stress disorder? Aust N Z J Psychiatry. 24:516– Thompson, A., Marwaha, S., Nelson, B., 528. Wood, S.J., McGorry, P.D., Yung, A.R, et al. (2016). Do affective or dissociative Steen, Y., Gimpel‐Drees, J., Lataster, T., symptoms mediate the association between Viechtbauer, W., Simons, C. J. P., Lardinois, childhood sexual trauma and transition to M., ... & Myin‐Germeys, I. (2017). Clinical psychosis in an ultra-high risk cohort? high risk for psychosis: the association Psychiatry Research. 236:182–5. between momentary stress, affective and doi:10.1016/j.psychres.2016.01.017 psychotic symptoms. Acta Psychiatrica Scandinavica, 136(1), 63-73. Thompson, A., Nelson, B., McNab, C., Simmons, M., Leicester, S., McGorry, P.D., Stowkowy, J., Addington, J. (2013). et al. (2010). Psychotic symptoms with Predictors of a clinical high risk status sexual content in the “ultra high risk” for among individuals with a family history of psychosis population: frequency and psychosis. Schizophrenia Research. 147(2– association with sexual trauma. Psychiatry 3):281–6. doi:10.1016/j.schres.2013.03.030 Research.177(1–2):84–91. doi:10.1016/j.psychres.2010.02.011 Stowkowy, J., Liu, L., Cadenhead, K.S., Thompson, A., Sullivan, S., Lewis, G., Cannon, T.D., Cornblatt, B.A., McGlashan, Zammit, S., Heron, J., Horwood, J., ... T.H., et al (2016). Early traumatic Harrison, G. (2011). Association between experiences, perceived discrimination and locus of control in childhood and psychotic conversion to psychosis in those at clinical symptoms in early adolescence: Results high risk for psychosis. Soc Psychiatry from a large birth cohort. Cognitive Psychiatr Epidemiol 51(4):497–503. Neuropsychiatry, 16(5), 385–402. doi:10.1007/s00127-016-1182-y Thompson, E., Kline, E., Ellman, L. M., Sugranyes, G., Thompson, J. L., & Mittal, V., Reeves, G. M., & Schiffman, J. Corcoran, C. M. (2012). HPA-axis function, (2015). Emotional and behavioral

Copyright © 2017, Archives of Psychology. All rights reserved. http://www.archivesofpsychology.org Redman S.L. et al. Archives of Psychology, vol. 1, issue 3, December 2017 Page 22 of 23 symptomatology reported by help-seeking Maltreatment 2014. (2016). Available from youth at clinical high-risk for psychosis. http://www.acf. Schizophrenia research, 162(1), 79-85. hhs.gov/programs/cb/research-data- technology/statistics-research/child- Thompson, P. M., Vidal, C., Giedd, J. N., maltreatment Gochman, P., Blumenthal, J., Nicolson, R., ... & Rapoport, J. L. (2001). Mapping van Dam, D. S., Van Der Ven, E., Velthorst, adolescent brain change reveals dynamic E., Selten, J. P., Morgan, C., & De Haan, L. wave of accelerated gray matter loss in very (2012). Childhood bullying and the early-onset schizophrenia. Proceedings of association with psychosis in non-clinical the National Academy of Sciences, 98(20), and clinical samples: A review and meta- 11650-11655. analysis. Psychological Medicine, 42(12), 2463–2474. Tikka, M., Luutonen, S., Ilonen, T., Tuominen, L., Kotimäki, M., Hankala, J., & van Dam, D. S., van Nierop, M., Salokangas, R. K. (2013). Childhood trauma Viechtbauer, W., Velthorst, E., van Winkel, and premorbid adjustment among R., Bruggeman, R., ... Wiersma, D. (2014a). individuals at clinical high risk for psychosis Childhood abuse and neglect in relation to and normal control subjects. Early the presence and persistence of psychotic intervention in psychiatry, 7(1), 51-57. and depressive symptomatology. Psychological Medicine, 45(7), 1363–1377. Trauelsen, A. M., Bendall, S., Jansen, J. E., Nielsen, H. G. L., Pedersen, M. B., Trier, C. van Dam, D. S., Korver-Nieberg, N., H., ... Simonsen, E. (2015). Childhood Velthorst, E., Meijer, C. J., & de Haan, L. adversity specificity and dose–response (2014b). Child- hood maltreatment, adult effect in non-affective first-episode attachment and psychotic symptomatology: psychosis. Schizophrenia Research, 165(1), A study in patients, siblings and controls. 52–59. Social Psychiatry and Psychiatric Epidemiology, 49(11), 1759–1767. Trotman, H. D., Holtzman, C. W., Walker, E. F., Addington, J. M., Bearden, C. E., Van Der Velde, J., Opmeer, E. M., Cadenhead, K. S., ... & Tsuang, M. T. Liemburg, E. J., Bruggeman, R., Nieboer, (2014). Stress exposure and sensitivity in the R., Wunderink, L., & Aleman, A. (2015). clinical high-risk syndrome: initial findings Lower prefrontal activation during emotion from the North American Prodrome regulation in subjects at ultrahigh risk for Longitudinal Study (NAPLS). Schizophrenia psychosis: an fMRI-study. npj research, 160(1), 104-109. Schizophrenia, 1, 15026. Üçok, A., Kaya, H., Ugurpala, C., Cikrikcili, Van Os, J., & Selten, J. P. (1998). Prenatal U., Ergul, C., Yokusoglu, C, et al. (2015). exposure to maternal stress and subsequent History of childhood physical trauma is schizophrenia. The May 1940 invasion of related to cognitive decline in individuals The Netherlands. The british journal of with ultra-high risk for psychosis. psychiatry, 172(4), 324-326. Schizophrenia Research. 169(1–3):199–203. doi:10.1016/j.schres.2015.08.038 van Winkel, R., Stefanis, N. C., & Myin- Germeys, I. (2008). Psychosocial stress and U.S. Department of Health and Human psychosis. A review of the neurobiological Services, Administration for Children and mechanisms and the evidence for gene-stress Families, Administration on Children Youth interaction. Schizophrenia bulletin, 34(6), and Families, Children‟s Bureau. Child 1095-1105

Copyright © 2017, Archives of Psychology. All rights reserved. http://www.archivesofpsychology.org Redman S.L. et al. Archives of Psychology, vol. 1, issue 3, December 2017 Page 23 of 23 van Winkel, R., van Nierop, M., Myin- risk youth. J Abnormal Psychol. 119:401– Germeys, I., & van Os, J. (2013). Childhood 408. trauma as a cause of psychosis: linking genes, psychology, and biology. The Walker EF, Trotman HD, Pearce BD, Canadian Journal of Psychiatry, 58(1), 44- Addington J, Cadenhead KS, Cornblatt BA, 51. et al. (2013). Cortisol levels and risk for psychosis: initial findings from the North Varese, F., Smeets, F., Drukker, M., American prodrome longitudinal study. Biol Lieverse, R., Lataster, T., Viechtbauer, W., Psychiatry 74(6):410–7. ... Bentall, R. P. (2012a). Childhood doi:10.1016/j.biopsych.2013.02.016 adversities increase the risk of psychosis: A meta-analysis of patient-control, Weickert CS, Hyde TM, Lipska BK, prospective-and cross-sectional cohort Herman MM, Weinberger DR, & Kleinman studies. Schizophrenia Bulletin, 38(4), 661– JE (2003) Reduced brain-derived 671. neurotrophic factor in prefrontal cortex of patients with schizophrenia. Mol Varese, F., Smeets, F., Drukker, M., Psychiatry 8: 592-610. Lieverse, R., Lataster, T., Viechtbauer, W., ... & Bentall, R. P. (2012). Childhood Wood, S. J., Pantelis, C., Proffitt, T., adversities increase the risk of psychosis: a Phillips, L. J., Stuart, G. W., Buchanan, J. meta-analysis of patient-control, A., ... & McGorry, P. D. (2003). Spatial prospective-and cross-sectional cohort working memory ability is a marker of risk- studies. Schizophrenia bulletin, 38(4), 661- for-psychosis. Psychological 671. medicine, 33(7), 1239-1247. Veras, A. B., Peixoto, C., Messinger, J. W., Woodberry, K. A., Seidman, L. J., Giuliano, Getz, M., Goetz, R., Buckley, P., ... & A. J., Verdi, M. B., Cook, W. L., & Kranz, T. M. (2017). Early trauma and McFarlane, W. R. (2010). clinical features of schizophrenia cases Neuropsychological profiles in individuals at influenced by the BDNF met clinical high risk for psychosis: relationship allele. Schizophrenia Research. to psychosis and intelligence. Schizophrenia research, 123(2), 188-198. Verdoux, H., Geddes, J. R., Takei, N., Lawrie, S. M., Bovet, P., Eagles, J. M., ... & Yung, A. R., & McGorry, P. D. (1996). The Stober, G. (1997). Obstetric complications initial prodrome in psychosis: descriptive and age at onset in schizophrenia: an and qualitative aspects. Australian and New international collaborative meta-analysis of Zealand Journal of Psychiatry, 30(5), 587- individual patient data. American Journal of 599. Psychiatry, 154(9), 1220-1227. Zuccato, C., Ciammola, A., Rigamonti, D., Walker E.F., Brennan, P.A., Esterberg, M., Leavitt, B. R., Goffredo, D., Conti, L., ... & Brasfield, J., Pearce, B., Compton, M.T. Timmusk, T. (2001). Loss of huntingtin- (2010). Longitudinal changes in cortisol mediated BDNF gene transcription in secretion and conversion to psychosis in at- Huntington's disease. Science, 293(5529), 493-498.