Abstract Negative symptoms of schizophrenia are associated with deficits in representing the value of actions, observed in reinforcement learning (RL) tasks as impaired learning from gains but intact learning from losses. This RL profile contrasts with depression, where enhanced loss sensitivity is common. Whether a schizophrenia-like RL pattern characterizes youth at clinical high-risk (CHR) for psychosis – who show modest psychosis transition rates but high rates of co-occurring depression – remains unclear. We tested whether CHR youth show a schizophrenia-like RL profile and whether RL parameters relate differentially to negative vs. depressive symptoms by estimating RL in CHR ( n = 292), clinical controls (CC; n = 241) with other psychopathologies, and healthy controls ( n = 175). Participants completed symptom interviews, neuropsychological assessments, a dimensional psychosis risk calculator, and an RL task in which participants could seek gains or avoid losses. A computational gain-loss Q -learning model decomposed task behavior into components indexing value updating and value-guided choice. Although overall RL performance was similar across groups, in both CHR and CC youth, higher negative, but not depressive symptoms, were selectively associated with reduced win-stay behavior following gains. Computational parameters suggested this behavioral pattern reflected disrupted updating and expression of positive value representations. Lower win-stay rates were also linked to lower premorbid intelligence and higher psychosis risk calculator scores. Here, a schizophrenia-like RL profile was unrelated to depression but associated with multiple indicators of psychosis risk across clinical groups, suggesting a transdiagnostic psychosis risk mechanism distinct from affective disturbance.

BACKGROUND:Posttraumatic stress disorder (PTSD) is a common comorbid diagnosis in psychotic disorders. However, little is known about the effect of comorbid PTSD in youth at clinical high risk (CHR) for psychosis. PURPOSE:The purpose of this study was to investigate group differences in symptom severity, risk for psychotic conversion and functioning among youth at CHR for psychosis with and without PTSD. METHODS:This longitudinal study utilized data from N = 693 individuals who met criteria for CHR as part of the North American Prodrome Longitudinal Study 3 (NAPLS-3). Individuals who met criteria for PTSD were compared to those who did not meet criteria for PTSD on demographic, symptom and functional variables. RESULTS:Individuals diagnosed with PTSD (N = 54) reported more severe overall positive symptoms (p = 0.008), negative symptoms (p = 0.043) and general symptoms (p = 0.008) compared to those without the diagnosis (N = 639). These symptom differences were primarily accounted for by more grandiose symptoms (p = 0.026), decreased experience of emotions (p = 0.043), sleep disturbance (p = 0.043), dysphoric mood (p = 0.012) and impaired tolerance to stress (p = 0.008) in those with PTSD. In Cox proportional hazards models using the full sample with censoring at last follow-up, PTSD diagnosis was not associated with time to psychosis conversion. Exploratory analyses of trauma subtype within the PTSD group also did not identify any trauma category significantly associated with conversion risk. Timing of trauma exposure (early childhood, middle childhood, adolescence) was not significantly associated with conversion. CONCLUSIONS:Our findings suggest that a diagnosis of PTSD is associated with more severe overlapping symptoms in individuals meeting the criteria for CHR but not psychotic conversion. Our findings underscore the importance of recognizing and treating comorbid psychiatric conditions including PTSD in CHR populations as a means of reducing symptoms and improving outcomes.

This chapter explores ongoing research in schizophrenia, focusing on the prodromal phase and the early course of the disorder. It emphasizes the importance of identifying neurocognitive and neuroimaging biomarkers that predict the onset of psychosis before full-blown symptoms emerge. The chapter highlights the need for studies on clinical characteristics, pathways to care, and neurodevelopmental processes that underlie psychosis. It also discusses the role of social cognition and brain imaging in understanding early psychosis and the influence of genetic factors, particularly in high-risk populations like those with the 22q11.2 deletion syndrome. Finally, the chapter stresses the potential of future precision medicine approaches, including multimodal interventions targeting non-dopaminergic pathways, to improve outcomes for individuals at risk of schizophrenia.

BACKGROUND AND HYPOTHESIS:Persistent distressing psychotic-like experiences (PLE) are associated with impaired functioning and future psychopathology. Prior research suggests that physical activities may be protective against psychopathology. However, it is unclear whether physical activities may interact with genetics in the development of psychosis. STUDY DESIGN:This study included 4679 participants of European ancestry from the Adolescent Brain Cognitive Development Study. Persistent distressing PLE was derived from the Prodromal-Questionnaire-Brief Child Version using four years of data. Generalized linear mixed models tested the association between polygenic risk score for schizophrenia (PRS-SCZ), physical activities, and PLE. The models adjusted for age, sex, parental education, income-to-needs ratio, family history of psychosis, body mass index, puberty status, principal components for PRS-SCZ, study site, and family. STUDY RESULTS:PRS-SCZ was associated with a greater risk for persistent distressing PLE (adjusted relative risk ratio (RRR) = 1.14, 95% CI [1.04, 1.24], P = .003). Physical activity was associated with less risk for persistent distressing PLE (adjusted RRR = 0.87, 95% CI [0.79, 0.96], P = .008). Moreover, physical activities moderated the association between PRS-SCZ and persistent distressing PLE (adjusted RRR = 0.89, 95% CI [0.81, 0.98], P = .015), such that the association was weaker as participants had greater participation in physical activities. CONCLUSIONS:These findings demonstrate that the interaction between genetic liability and physical activities is associated with trajectories of distressing PLE. Further research is needed to understand the mechanisms of physical activities and genetic liability for schizophrenia in the development of psychosis.

This chapter discusses the prevention of schizophrenia, emphasizing early intervention strategies to identify individuals at risk during childhood and adolescence. It introduces a classification system for prevention, which includes primary, secondary, and tertiary approaches, and distinguishes between universal, selective, and indicated prevention strategies. The chapter explains that while risk factors such as family history and birth complications are well-established, recent research focuses on identifying clinical high-risk signs that may emerge during the prodromal phase. Researchers identify several neurodevelopmental and behavioral precursors of schizophrenia, including motor dysfunctions, attention deficits, and social withdrawal, which often begin in infancy. Finally, the chapter stresses the need to refine screening tools and interventions, as current methods have limitations in predicting who will develop schizophrenia.

This chapter defines schizophrenia as a severe neurodevelopmental disorder with onset typically in adolescence or early adulthood and examines its diagnostic criteria, phenomenology, and links to neurobiology. It compares DSM and ICD diagnostic systems, highlights challenges in adolescent diagnosis due to comorbidities and substance use, and emphasizes the importance of developmental context in symptom assessment. The chapter explores early signs of psychosis in clinical high-risk youth, describes neural and cognitive impairments, and connects symptoms to brain circuitry through neuroimaging, electrophysiology, and genetics. It underscores adolescence as a critical period due to hormonal changes, stress sensitivity, and ongoing brain maturation that influence psychosis risk. Finally, the chapter emphasizes integrating neurodevelopmental, genetic, and environmental models to understand the pathophysiology of schizophrenia and guide early detection, intervention, and prevention strategies.

BACKGROUND AND HYPOTHESIS:Despite significant advances in our understanding of the clinical high risk (CHR) for psychosis state, the longer-term outcomes (5+ years) and the trajectory of diagnoses, symptoms, and psychosocial function have been seldom investigated. OBJECTIVE:Here we describe the methods for "Predictors and Moderators of Long-Term Outcome of Persons at Clinical High Risk for Psychosis," an ongoing study that is being conducted across North American Prodrome Longitudinal Studies sites that included n = 2184 past participants (1999-2018). STUDY DESIGN:The aims are to: (1) perform long-term assessments of individuals who previously met CHR criteria, (2) determine the 5+ year psychotic conversion rate and use previously collected longitudinal clinical, functional, neurocognitive, and biomarker data to predict longer term outcomes, and (3) investigate predictors of long-term clinical/functional outcome in CHR participants who did not convert to psychosis. STUDY RESULTS:Preliminary results from the first n = 504 participants demonstrate that 60% of those who previously met CHR criteria are still symptomatic. Eighteen percent of past participants converted to psychosis, half in the original studies and the remainder since last evaluated. Of those who converted to psychosis, the majority met criteria for an affective psychosis, consistent with the high rate of affective disorders (70%) in the non-converted group. An additional 7% of past participants died, substantially higher than the general population. CONCLUSIONS:These early data highlight the potential of how this dataset, when combined with baseline data, can be used to answer new questions about the life course of high-risk youth and how we might intervene early to improve their long-term outcome.

This chapter discusses the treatment of schizophrenia, particularly in the context of first-episode psychosis (FEP). It highlights the importance of early intervention, including the use of the Coordinated Specialty Care (CSC) model, which has proven more effective than traditional treatment approaches. The chapter outlines the stages of schizophrenia, from the prodromal phase to the first psychotic episode, stressing the benefits of early treatment for better long-term outcomes. It also addresses pharmacological treatments, focusing on second-generation antipsychotics, and emphasizes challenges such as medication adherence and the treatment of negative and cognitive symptoms. Finally, the chapter emphasizes the importance of preventing psychosis in individuals at high risk and underscores the need for ongoing research to refine treatment strategies.