Joseph Kambeitz

Background and Hypothesis: Clinical high risk (CHR) for psychosis status is associated with poor social functioning. Previous studies suggest that childhood trauma and reduced amplitude of the P300 event-related potential (ERP) component elicited by infrequent target stimuli (P3b) are associated with poor social function. Here, we examined whether reduced P3b mediates the relationship between reported trauma history and social function in CHR individuals, possibly reflecting the impact of past trauma on neurophysiological processes subserving attention that ultimately influence social functioning. Study Design: Target P3b ERP amplitudes from visual and auditory oddball tasks acquired at baseline in the Accelerating Medicines Partnership® Schizophrenia (AMP SCZ) study were analyzed. The mediating effects of auditory and visual P3b amplitude on the relationship between trauma history (Childhood Trauma Questionnaire total score) and Negative Symptom Inventory-Psychosis Risk Asociality (NSI-PR) as well as social functioning (Global Functioning: Social (GFS) scores were examined. Study Results: Data from 931 CHR participants (average age 21.29 years, 36.3% male) were included in mediation analyses. Visual P3b showed significant (p < .05) mediation of the relationship between trauma load and GFS score (5.4% mediation) as well as mediation of the relationship between trauma history and NSI-PR asociality (9.3% mediation). Auditory P3b did not significantly mediate either relationship. Conclusions: These results suggest that visual, but not auditory, P3b mediates the relationship between past trauma load and social functioning in CHR, suggesting the effect of trauma on the neurophysiological processes subserving visual target detection may contribute to social functioning deficits in CHR individuals.

Childhood adversities and trauma (CAT) are linked to cognitive impairment, but their effects may vary across clinical profiles and in the presence of ongoing environmental stressors. We investigated CAT-cognition associations across recent-onset psychosis (ROP), clinical high risk for psychosis (CHR), recent-onset depression (ROD), and healthy controls (HC), and whether recent life events and perceived discrimination moderated these associations. We used baseline data from the PRONIA cohort (ROP: N = 150; CHR: N = 142; ROD: N = 148; HC: N = 282). Cognitive performance was assessed across social cognition, speed of processing, working and verbal memory, attention, and global cognition. Associations were tested using covariate-adjusted linear regression models based on HC-derived normative residualization, followed by moderation analyses. In ROP, higher CAT were associated with increased speed of processing (β = 0.29, p _fdr = .046). In CHR, CAT was associated with poorer social cognition, but higher attention and working memory scores (b = -0.20 to 0.44, p _fdr ≤ .042). In HC, increased physical neglect was associated with poorer attention (b = -0.64, p _fdr < .001). Perceived discrimination moderated associations between emotional abuse and attention in the ROP group (β = -4.721, 95% CI [-7.81, -1.63]), and between emotional abuse and social cognition in the ROD group (β = 7.834, 95% CI [2.430, 13.238]). CAT-cognition associations were heterogeneous across clinical groups, with perceived discrimination moderating specific associations. Relationships between CAT, particularly emotional neglect, and cognitive performance is not uniform but may vary depending on clinical context and ongoing psychosocial stressors.

Introduction: Suicidal ideation and behaviors (SIB) are common among individuals at clinical high risk for psychosis (CHR‐P), but their relationship with the overall clinical profile remains unclear. This study aimed to identify sociodemographic/clinical factors associated with SIB in CHR‐P individuals and to examine whether subthreshold psychotic symptom severity increases with suicidal risk. Methods: Data from the AMP SCZ initiative included 1443 CHR‐P participants aged 12–30 years. SIB were assessed using the Columbia Suicide Severity Rating Scale (C‐SSRS). Three Elastic Net regression models examined associations between suicidal ideation severity, intensity, and behaviors using 54 variables spanning sociodemographics, general psychopathology, subthreshold psychotic symptoms, and socio‐occupational functioning. Moreover, ANCOVA compared overall psychotic symptom severity across five groups defined by increasing severity on the C‐SSRS. Results: Sixty‐eight percent of participants reported lifetime suicidal ideation, and 26% reported previous suicidal behaviors. Model performance was modest but significant (cross‐validated ideation severity: R ² = 0.161, RMSE = 0.916; ideation intensity: R ² = 0.193, RMSE = 0.898; suicidal behavior: accuracy = 0.685; AUC = 0.675; p < 0.001). Across all models, concurrent depressive symptoms, present/past diagnosis of depression, female sex at birth, cannabis use, visual/gustatory abnormalities, guilt, and lower role functioning were the most consistent correlates of SIB. Ideation was associated with lower disorganized communication expression and lower negative symptoms, whereas behaviors were associated with schizotypal personality disorder. Other core CHR‐P symptoms, including Unusual Thoughts and Experiences, did not contribute to any model. ANCOVA ( p < 0.001, partial η ² = 0.041) indicated increasing overall subthreshold psychotic symptoms across the SIB spectrum. Conclusion: SIB in CHR‐P individuals reflects a multidimensional clinical profile primarily outside of core psychosis‐risk symptoms. Trial Registration: ClinicalTrials.gov identifier: NCT05905003

White matter (WM) alterations are well documented in individuals at clinical high-risk for psychosis (CHR-P) and with recent-onset psychosis (ROP), yet it remains unclear whether they reflect vulnerability, psychosis-related symptom severity, or general impairments shared with other disorders such as depression. To disentangle these correlates, we analyzed diffusion MRI data from 882 individuals (457 females) of the multisite Personalized Prognostic Tools for Early Psychosis Management (PRONIA) study, including 183 CHR-P, 206 ROP, 298 healthy controls, and 195 individuals with depression who were assessed as a clinical comparison group of observed associations. Fractional anisotropy (FA) was extracted from 25 WM regions. Analyses of covariance tested group differences across CHR-P, ROP, and healthy controls. Canonical correlation analysis then identified multivariate correlation components between FA and a broad set of twelve clinical, two cognitive, and two risk-related measures in CHR-P and ROP, restricted to regions with group effects. To identify if these findings are not specific to psychosis, we additionally tested whether the correlation components were expressed in the depression comparison group. Group differences emerged in 17 of 25 regions. Canonical correlation analysis identified two significant correlation components. Component 1 linked widespread lower FA with impaired cognition and functioning, representing general impairment. Component 2 linked focal lower FA with more severe psychosis-related symptoms and absence of familial risk. Component 1, but not Component 2, showed also a significant association in the depression group emphasizing its relevance for general impairment. Disentangling general impairment from psychosis-related symptom severity suggests potentially different underlying processes. Developing imaging biomarkers accounting for these processes may guide early detection strategies and targeted interventions.

Individuals with psychosis and depression show widespread alterations in brain resting-state functional connectivity (rs-FC), affecting both sensory and higher-order brain regions. In this study, we investigate disruptions in the hierarchical organization of brain functional networks in individuals with psychotic and affective disorders. We derived functional brain gradients, low dimensional representations of rs-FC that capture cortical hierarchy, in a sample of 1071 (56.3% female) participants, including clinical high-risk for psychosis (CHR-P) individuals, recent-onset psychosis (ROP) patients, recent-onset depression (ROD) patients, and healthy controls (HC). We examined regional alterations, network-level alterations and functional differentiation and their relationship to clinical symptoms. In addition, we linked case-control differences to receptor expression maps to explore underlying neurobiological mechanisms. All clinical groups exhibited alterations in the visual-to-sensorimotor gradient, while only ROP patients showed alterations in the sensory-to-association gradient. CHR-P and ROP individuals exhibited lower values in the ventral attention network. Clinical groups combined showed higher values in the somatomotor network, a reduced gradient range and altered between-network dispersion. ROD patients showed reduced within-network dispersion in the attentional networks and a reduced range. Correlational analysis revealed weak associations of gradient measures with functioning, visual dysfunctions and cognition. Case-control differences showed associations to receptor expression maps, suggesting the involvement of neurotransmitter systems in these disruptions. Our findings reveal transdiagnostic and disease-specific alterations of hierarchical brain organization. These alterations indicate deficits in functional integration across psychiatric diseases, highlighting the role of attentional and sensory networks in disease processes.

Sleep disturbance is a well-established risk factor for suicide, though few studies to date have examined whether sleep disturbance contributes to suicide risk among individuals at clinical high risk for psychosis (CHR). The current study addressed this gap in the literature. We hypothesized that sleep disturbance would have a unique relationship with suicidal ideation/attempts when accounting for other variables in the model. We also hypothesized that the interaction between sleep disturbance/attenuated positive symptoms and sleep disturbance/stress would be related to suicidal ideation/attempts in CHR. The current study used data generated by the Accelerating Medicines Partnership® Schizophrenia Observational Study. The total sample included 1,048 participants (827 CHR and 221 community controls). Participants completed measures of suicidal ideation/attempts, attenuated positive symptoms, depressive symptoms, perceived stress, and sleep disturbance. Results supported a relationship between sleep disturbance and suicidal ideation/attempts in CHR, with participants who had lifetime ideation and attempts experiencing more sleep disturbance than those with no ideation or attempts. We also found small, but significant positive correlations between sleep disturbance and suicide risk in CHR. When accounting for other variables in the model, the effect of sleep disturbance remained significant for past month ideation, but not lifetime ideation or attempts. Both interaction models were non-significant. Our findings highlight the potential value of sleep measures in early identification and treatment of suicide risk in CHR. Further research in this area is warranted.

Background and Hypothesis: Processing speed and verbal learning are linked to functioning in people at clinical high-risk for psychosis (CHR-P). However, a clear understanding of these relationships has been limited by the use of single-value assessor ratings of functioning and limited incorporation of self-report and longitudinal functional assessments. This study aims to examine the effect of processing speed and verbal learning on longitudinal assessor-rated and self-reported functioning. Study Design: Individuals at CHR-P (n = 1282) and community controls (n = 425) who participated in Accelerating Medicines Partnership—Schizophrenia were examined. Processing speed and verbal learning abilities were ascertained using the Penn Computerized Neurocognitive Battery. Assessor-rated functioning was measured using the Global Functioning Scales. Self-reported functioning was collected using Ecological Momentary Assessment. Analyses were linear models and mixed-effects models. Study Results: Both processing speed and verbal learning were associated with assessor-rated functioning at baseline and through 2 months (Ps < 0.001). Processing speed abilities predicted changes in self-reported ability to function (P = .036), motivation (P = .040), and concentration (P = .020) over time. Verbal learning abilities predicted changes in self-reported loneliness (P = .044) over time. Processing speed and verbal learning were associated with assessor-rated and self-reported functioning over and above estimated intelligence quotient and positive symptoms. Conclusions: Processing speed and verbal learning are important predictors of short-term longitudinal functioning, and may be important targets for early recognition and mitigation of psychosis risk.

Background: Language disturbances in psychotic and affective disorders persist beyond general cognitive dysfunction, yet the diagnostic value of computationally derived linguistic features relative to standard cognitive assessment remains unclear.Aims: To evaluate whether features derived using natural language processing (NLP) methods from a brief verbal fluency task (VFT) allow classification of early-stage psychotic and affective disorders or if language-based classifiers demonstrate transdiagnostic generalizability.Methods: Forty individuals with recent-onset psychosis (ROP), 50 with recent-onset depression (ROD), 33 at clinical high-risk for psychosis (CHR), and 54 healthy controls (HC) from the PRONIA study were investigated. Sixty-two NLP features were extracted from verbal fluency tasks. Five elastic net classifiers were evaluated using nested cross-validation, with cross-group transfer and staging analyses assessing severity across the four groups.Results: NLP-only models achieved classification accuracy comparable to a four-domain cognitive battery (MCCB) across all comparisons (pFDR > 0.54). Classifiers trained on one diagnostic comparison generalized to others. Staging analysis confirmed the predicted dimensional ordering HC < ROD = CHR < ROP. Group differences were driven by verbal productivity and search organization rather than semantic coherence.Conclusions: A two-minute verbal fluency assessment with automated NLP analysis matches a comprehensive cognitive battery for diagnostic classification. Linguistic features capture a differential-diagnostic marker that generalizes across diagnostic boundaries and reflects a dimensional severity gradient, supporting their integration into clinical screening or monitoring for early psychotic and affective disorders.