Clinical High Risk Individuals Research Articles

Advancements and Future Directions in Prevention Based on Evaluation for Individuals With Clinical High Risk of Psychosis: Insights From the SHARP Study.

This review examines the evolution and future prospects of prevention based on evaluation (PBE) for individuals at clinical high risk (CHR) of psychosis, drawing insights from the SHARP (Shanghai At Risk for Psychosis) study. It aims to assess the effectiveness of non-pharmacological interventions in preventing psychosis onset among CHR individuals. The review provides an overview of the developmental history of the SHARP study and its contributions to understanding the needs of CHR individuals. It explores the limitations of traditional antipsychotic approaches and introduces PBE as a promising framework for intervention. Three key interventions implemented by the SHARP team are discussed: nutritional supplementation based on niacin skin response blunting, precision transcranial magnetic stimulation targeting cognitive and brain functional abnormalities, and cognitive behavioral therapy for psychotic symptoms addressing symptomatology and impaired insight characteristics. Each intervention is evaluated within the context of PBE, emphasizing the potential for tailored approaches to CHR individuals. The review highlights the strengths and clinical applications of the discussed interventions, underscoring their potential to revolutionize preventive care for CHR individuals. It also provides insights into future directions for PBE in CHR populations, including efforts to expand evaluation techniques and enhance precision in interventions.

Diminished differentiation of rewards in individuals at clinical high-risk for psychosis.

Reward processing is impaired in people with schizophrenia, which may begin in the clinical high-risk (CHR) for psychosis period. The Monetary Incentive Delay (MID) task has been important in understanding the neural correlates of reward processing deficits in various psychiatric disorders. Previous research has found that CHR individuals have an imprecise mental representation of rewards, which leads to a diminished differentiation between rewards, though this has not been observed behaviorally. A total of 19 CHR individuals and 20 controls were given a novel variant of the MID task, designed to examine how modulating reward context may impact responses to reward cues, a process often referred to as "adaptive coding." Both groups appeared to update their behavior in response to the rewards available in this adaptive task. However, when compared to controls who showed a more graded decrease in response time to increasing reward contexts, CHR individuals appeared to have a sharp decrease in response time in the low reward context that is nearly stable across higher reward contexts. This is largely driven by the exponential component of the response time distribution, which is often interpreted to be more cognitively or effortfully influenced. Response times are related to negative symptoms, but not positive symptoms, disorganized symptoms, or estimated intelligence. Although an adaptive coding effect was not observed, these results provide novel insight into the reward processing mechanisms and volitional processes in the CHR population, as this was the first study to observe the diminished differentiation of rewards behaviorally.

Alteration in left frontoparietal connectivity correlates with impaired cognitive reappraisal in early psychosis

BackgroundImpaired cognitive reappraisal is a notable symptom of early psychosis, but its neurobiological basis remains underexplored. We aimed to identify the underlying neurobiological mechanism of this impairment by using resting-state functional connectivity (FC) analyses focused on brain regions related to cognitive reappraisal. MethodsResting-state functional magnetic resonance images were collected from 36 first-episode psychosis (FEP) patients, 32 clinical high-risk (CHR) individuals, and 48 healthy controls (HCs). Whole-brain FC maps using seed regions associated with cognitive reappraisal were generated and compared across the FEP, CHR and HC groups. We assessed the correlation between resting-state FC, reappraisal success ratio, positive symptom severity and social functioning controlling for covariates. ResultsFEP patients showed higher FC between the left superior parietal lobe and left inferior frontal gyrus than HCs. Higher FC between the left superior parietal lobe and left inferior frontal gyrus negatively correlated with the reappraisal success ratio in the FEP group after controlling for covariates. Lower FC correlated with lower positive symptom severity and improved global functioning in the FEP group. ConclusionsAlteration in left frontoparietal connectivity reflects impaired cognitive reappraisal in early psychosis, and such alteration correlates with increased positive symptoms and decreased global functioning. These findings offer a potential path for interventions targeting newly emerging symptoms in the early stages of psychosis.

Accelerating Medicines Partnership® Schizophrenia (AMP® SCZ): Rationale and Study Design of the Largest Global Prospective Cohort Study of Clinical High Risk for Psychosis.

This article describes the rationale, aims, and methodology of the Accelerating Medicines Partnership® Schizophrenia (AMP® SCZ). This is the largest international collaboration to date that will develop algorithms to predict trajectories and outcomes of individuals at clinical high risk (CHR) for psychosis and to advance the development and use of novel pharmacological interventions for CHR individuals. We present a description of the participating research networks and the data processing analysis and coordination center, their processes for data harmonization across 43 sites from 13 participating countries (recruitment across North America, Australia, Europe, Asia, and South America), data flow and quality assessment processes, data analyses, and the transfer of data to the National Institute of Mental Health (NIMH) Data Archive (NDA) for use by the research community. In an expected sample of approximately 2000 CHR individuals and 640 matched healthy controls, AMP SCZ will collect clinical, environmental, and cognitive data along with multimodal biomarkers, including neuroimaging, electrophysiology, fluid biospecimens, speech and facial expression samples, novel measures derived from digital health technologies including smartphone-based daily surveys, and passive sensing as well as actigraphy. The study will investigate a range of clinical outcomes over a 2-year period, including transition to psychosis, remission or persistence of CHR status, attenuated positive symptoms, persistent negative symptoms, mood and anxiety symptoms, and psychosocial functioning. The global reach of AMP SCZ and its harmonized innovative methods promise to catalyze the development of new treatments to address critical unmet clinical and public health needs in CHR individuals.

Clinical high risk state of major depressive episodes: Assessment of prodromal phase, its occurrence, duration and symptom patterns by the instrument the DEpression Early Prediction-INventory (DEEP-IN)

BackgroundTo decrease the incidence of major depressive episodes, indicated prevention that targets clinical high-risk individuals with first detectable signs that forecast mental disorder is a highly relevant topic of preventive psychiatry. Still little is known about the prodrome of MDE. The aim of the current study was to identify the occurrence of a clinical high-risk state of depression, its duration and symptom constellation. MethodsSeventy-three patients with a diagnosed affective disorder in partial remission were assessed with our newly developed semi-structured extensive clinical instrument, the DEpression Early Prediction-INventory (DEEP-IN). Within DEEP-IN the course of prodromal symptoms was explored by using a life-chart method. ResultsThe significant majority of patients (93.2 %) reported a prodromal phase. The mean duration was 7.9 months (SD = 12.5). Within the group with an identified prodromal phase, psychopathological (95.6 %) as well as somatic symptoms (88.2 %) were reported. Somatic symptoms showed a moderate-to-strong effect of sex with higher prevalence in females than in males (97.6 % vs 73.1 %; V = 0.370). LimitationsThis feasibility study had only a small sample size. ConclusionsThe majority of patients with affective disorders reported a clinical prodromal phase with both psychopathological and somatic symptoms that developed months before the onset of the depressive episode. The development of structured instruments for the assessment of depressive risk states is a promising approach for indicated prevention of depression in the future.

Aberrant brain dynamics in individuals with clinical high risk of psychosis.

Resting-state network (RSN) functional connectivity analyses have profoundly influenced our understanding of the pathophysiology of psychoses and their clinical high risk (CHR) states. However, conventional RSN analyses address the static nature of large-scale brain networks. In contrast, novel methodological approaches aim to assess the momentum state and temporal dynamics of brain network interactions. Fifty CHR individuals and 33 healthy controls (HC) completed a resting-state functional MRI scan. We performed an Energy Landscape analysis, a data-driven method using the pairwise maximum entropy model, to describe large-scale brain network dynamics such as duration and frequency of, and transition between, different brain states. We compared those measures between CHR and HC, and examined the association between neuropsychological measures and neural dynamics in CHR. Our main finding is a significantly increased duration, frequency, and higher transition rates to an infrequent brain state with coactivation of the salience, limbic, default mode and somatomotor RSNs in CHR as compared to HC. Transition of brain dynamics from this brain state was significantly correlated with processing speed in CHR. In CHR, temporal brain dynamics are attracted to an infrequent brain state, reflecting more frequent and longer occurrence of aberrant interactions of default mode, salience, and limbic networks. Concurrently, more frequent and longer occurrence of the brain state is associated with core cognitive dysfunctions, predictors of future onset of full-blown psychosis.

Adjunctive canakinumab reduces peripheral inflammation markers and improves positive symptoms in people with schizophrenia and inflammation: A randomized control trial

BackgroundClinical trials of anti-inflammatories in schizophrenia do not show clear and replicable benefits, possibly because patients were not recruited based on elevated inflammation status. Interleukin 1-beta (IL-1β) mRNA and protein levels are increased in serum, plasma, cerebrospinal fluid, and brain of some chronically ill patients with schizophrenia, first episode psychosis, and clinical high-risk individuals. Canakinumab, an approved anti-IL-1β monoclonal antibody, interferes with the bioactivity of IL-1β and interrupts downstream signaling. However, the extent to which canakinumab reduces peripheral inflammation markers, such as, high sensitivity C-reactive protein (hsCRP) and symptom severity in schizophrenia patients with inflammation is unknown. Trial designWe conducted a randomized, placebo-controlled, double-blind, parallel groups, 8-week trial of canakinumab in chronically ill patients with schizophrenia who had elevated peripheral inflammation. MethodsTwenty-seven patients with schizophrenia or schizoaffective disorder and elevated peripheral inflammation markers (IL-1β, IL-6, hsCRP and/or neutrophil to lymphocyte ratio: NLR) were randomized to a one-time, subcutaneous injection of canakinumab (150 mg) or placebo (normal saline) as an adjunctive antipsychotic treatment. Peripheral blood hsCRP, NLR, IL-1β, IL-6, IL-8 levels were measured at baseline (pre injection) and at 1-, 4- and 8-weeks post injection. Symptom severity was assessed at baseline and 4- and 8-weeks post injection. ResultsCanakinumab significantly reduced peripheral hsCRP over time, F(3, 75) = 5.16, p = 0.003. Significant hsCRP reductions relative to baseline were detected only in the canakinumab group at weeks 1, 4 and 8 (p’s = 0.0003, 0.000002, and 0.004, respectively). There were no significant hsCRP changes in the placebo group. Positive symptom severity scores were significantly reduced at week 8 (p = 0.02) in the canakinumab group and week 4 (p = 0.02) in the placebo group. The change in CRP between week 8 and baseline (b = 1.9, p = 0.0002) and between week 4 and baseline (b = 6.0, p = 0.001) were highly significant predictors of week 8 change in PANSS Positive Symptom severity scores. There were no significant changes in negative symptoms, general psychopathology or cognition in either group. Canakinumab was well tolerated and only 7 % discontinued. ConclusionsCanakinumab quickly reduces peripheral hsCRP serum levels in patients with schizophrenia and inflammation; after 8 weeks of canakinumab treatment, the reductions in hsCRP are related to reduced positive symptom severity. Future studies should consider increased doses or longer-term treatment to confirm the potential benefits of adjunctive canakinumab in schizophrenia.Australian and New Zealand Clinical Trials Registry number: ACTRN12615000635561.

Speech characteristics yield important clues about motor function: Speech variability in individuals at clinical high-risk for psychosis

Background and hypothesis: Motor abnormalities are predictive of psychosis onset in individuals at clinical high risk (CHR) for psychosis and are tied to its progression. We hypothesize that these motor abnormalities also disrupt their speech production (a highly complex motor behavior) and predict CHR individuals will produce more variable speech than healthy controls, and that this variability will relate to symptom severity, motor measures, and psychosis-risk calculator risk scores. Study design: We measure variability in speech production (variability in consonants, vowels, speech rate, and pausing/timing) in N = 58 CHR participants and N = 67 healthy controls. Three different tasks are used to elicit speech: diadochokinetic speech (rapidly-repeated syllables e.g., papapa…, pataka…), read speech, and spontaneously-generated speech. Study results: Individuals in the CHR group produced more variable consonants and exhibited greater speech rate variability than healthy controls in two of the three speech tasks (diadochokinetic and read speech). While there were no significant correlations between speech measures and remotely-obtained motor measures, symptom severity, or conversion risk scores, these comparisons may be under-powered (in part due to challenges of remote data collection during the COVID-19 pandemic). Conclusion: This study provides a thorough and theory-driven first look at how speech production is affected in this at-risk population and speaks to the promise and challenges facing this approach moving forward.

Functional connectivity in people at clinical and familial high risk for schizophrenia

Patients diagnosed with schizophrenia (SZ) exhibit compromised functional connectivity within extensive brain networks. However, the precise development of this impairment during disease progression in the clinical high-risk (CHR) population and their relatives remains unclear. Our study leveraged data from 128 resting electroencephalography (EEG) channels acquired from 30 SZ patients, 21 CHR individuals, 17 unaffected healthy relatives (RSs; those at heightened SZ risk due to family history), and 31 healthy controls (HCs). These data were harnessed to establish functional connectivity patterns. By calculating the geometric distance between EEG sequences, we unveiled local and global nonlinear relationships within the entire brain. The process of dimensionality reduction led to low-dimensional representations, providing insights into high-dimensional EEG data. Our findings indicated that CHR participants exhibited aberrant functional connectivity across hemispheres, whereas RS individuals showcased anomalies primarily concentrated within hemispheres. In the realm of low-dimensional analysis, RS participants' third-dimensional occipital lobe values lay between those of the CHR individuals and HCs, significantly correlating with scale scores. This low-dimensional approach facilitated the visualization of brain states, potentially offering enhanced comprehension of brain structure, function, and early-stage functional impairment, such as occipital visual deficits, in RS individuals before cognitive decline onset.

Serum Levels of Tumor Necrosis Factor-α and Vascular Endothelial Growth Factor in the Subtypes of Clinical High Risk Individuals: A Prospective Cohort Study [Response to Letter

Serum Levels of Tumor Necrosis Factor-α and Vascular Endothelial Growth Factor in the Subtypes of Clinical High Risk Individuals: A Prospective Cohort Study [Response to Letter

Serum Levels of Tumor Necrosis Factor-α and Vascular Endothelial Growth Factor in the Subtypes of Clinical High Risk Individuals: A Prospective Cohort Study [Letter

Serum Levels of Tumor Necrosis Factor-α and Vascular Endothelial Growth Factor in the Subtypes of Clinical High Risk Individuals: A Prospective Cohort Study [Letter

Differential Expression of Anomalous Self-Experiences in Spontaneous Speech in Clinical High-Risk and Early-Course Psychosis Quantified by Natural Language Processing

BackgroundBasic self-disturbance, or anomalous self-experiences (ASEs), is a core feature of the schizophrenia spectrum. We propose a novel method of natural language processing to quantify ASEs in spoken language by direct comparison to an inventory of self-disturbance, the Inventory of Psychotic-Like Anomalous Self-Experiences (IPASE). We hypothesized that there would be increased similarity in open-ended speech to the IPASE items in individuals with early-course psychosis (PSY) compared with healthy individuals, with clinical high-risk (CHR) individuals intermediate in similarity. MethodsOpen-ended interviews were obtained from 170 healthy control participants, 167 CHR participants, and 89 PSY participants. We calculated the semantic similarity between IPASE items and “I” sentences from transcribed speech samples using S-BERT (Sentence Bidirectional Encoder Representation from Text). Kolmogorov-Smirnov tests were used to compare distributions across groups. A nonnegative matrix factorization of cosine similarity was performed to rank IPASE items. ResultsSpoken language of CHR individuals had the greatest semantic similarity to IPASE items when compared to both healthy control (s = 0.44, p < 10−14) and PSY (s = 0.36, p < 10−6) individuals, while IPASE scores were higher among PSY than CHR group participants. In addition, the nonnegative matrix factorization approach produced a data-driven domain that differentiated the CHR group from the others. ConclusionsWe found that open-ended interviews elicited language with increased semantic similarity to the IPASE by participants in the CHR group compared with patients with psychosis. This demonstrates the utility of these methods for differentiating patients from healthy control participants. This complementary approach has the capacity to scale to large studies investigating phenomenological features of schizophrenia and potentially other clinical populations.

Serum Levels of Tumor Necrosis Factor-α and Vascular Endothelial Growth Factor in the Subtypes of Clinical High Risk Individuals: A Prospective Cohort Study.

Numerous studies have established the roles of inflammation and angioneurins in the pathogenesis of schizophrenia (SCZ). This study aimed to compare the serum levels of tumour necrosis factor (TNF)-α and vascular endothelial growth factor (VEGF) in patients at clinical high risk (CHR) for psychosis or SCZ at baseline and one year after treatment. A total of 289 CHR participants from the Shanghai At Risk for Psychosis Extended Program (SHARP) were tracked for a year. They were divided into two and four subtypes based on symptom severity according to the Structured Interview for Prodromal Syndromes (SIPS) and received standard medical care. At baseline and one-year follow-up, TNF-α and VEGF were detected using enzyme-linked immunosorbent assay, and pathological features were assessed using the Global Assessment of Function (GAF) score. Baseline TNF-α levels did not differ significantly, while VEGF levels were lower in patients with more severe symptoms. VEGF showed a negative correlation with negative features, both overall (r = -0.212, p = 0.010) and in the subgroup with higher positive scores (r = -0.370, p = 0.005). TNF-α was positively correlated with negative symptoms in the subgroup with higher negative scores (r = 0.352, p = 0.002). A three-way multivariate analysis of variance demonstrated that participants in Subtype 1 of positive or negative symptoms performed better than those in Subtype 2, with significant main effects and interactions of group and both cytokines. TNF-α and VEGF levels are higher and lower, respectively, in CHR patients with more severe clinical symptoms, particularly negative symptoms, which point to a worsening inflammatory and vascular status in the brain.

Sampling from different populations: Sociodemographic, clinical, and functional differences between samples of first episode psychosis individuals and clinical high-risk individuals who progressed to psychosis.

Over the past two decades, research and clinical resources on clinical high risk (CHR) for psychosis have both expanded, with goals to better understanding risk and protective factors on the course of illness and inform early intervention efforts. However, some studies have highlighted potential sampling bias among CHR research studies, raising questions about generalizability of findings and inequitable access to early detection and intervention. The current study sought to explore these questions by comparing 94 participants in a CHR longitudinal monitoring study across North America (NAPLS-2) who converted to syndromal psychosis over the course of the study (CHR-CV) to 171 participants who presented for treatment at a localized first-episode psychosis service (FES) after converting. CHR-CV participants were significantly more likely to be White and have a college-educated parent, while FES participants were more likely to be Black and first- or second-generation immigrants. On average, CHR-CV participants were younger at onset of attenuated positive symptoms, had a longer period of attenuated symptoms prior to conversion, and were more likely to be treated with antipsychotics prior to conversion compared to those in FES programs. After controlling for time since conversion, CHR-CV participants had higher global functioning and were less likely to have experienced recent psychiatric hospitalization. Findings suggest that CHR research and FES clinics may be sampling from different populations, although conclusions are limited by inconsistent sampling frames and methods. Integrated early detection that targets defined geographic catchments may deliver more epidemiologically representative samples to both CHR research and FES.

N-Acetylaspartate and Choline Metabolites in Cortical and Subcortical Regions in Clinical High Risk Relative to Healthy Control Subjects: An Exploratory 7T MRSI Study.

N-acetylaspartate (NAA) and choline (Cho) are two brain metabolites implicated in several key neuronal functions. Abnormalities in these metabolites have been reported in both early course and chronic patients with schizophrenia (SCZ). It is, however, unclear whether NAA and Cho's alterations occur even before the onset of the disorder. Clinical high risk (CHR) individuals are a population uniquely enriched for psychosis and SCZ. In this exploratory study, we utilized 7-Tesla magnetic resonance spectroscopic imaging (MRSI) to examine differences in total NAA (tNAA; NAA + N-acetylaspartylglutamate [NAAG]) and major choline-containing compounds, including glycerophosphorylcholine and phosphorylcholine [tCho], over the creatine (Cre) levels between 26 CHR and 32 healthy control (HC) subjects in the subcortical and cortical regions. While no tCho/Cre differences were found between groups in any of the regions of interest (ROIs), we found that CHR had significantly reduced tNAA/Cre in the right dorsal lateral prefrontal cortex (DLPFC) compared to HC, and that the right DLPFC tNAA/Cre reduction in CHR was negatively associated with their positive symptoms scores. No tNAA/Cre differences were found between CHR and HC in other ROIs. In conclusion, reduced tNAA/Cre in CHR vs. HC may represent a putative molecular biomarker for risk of psychosis and SCZ that is associated with symptom severity.

Ethnoracial discrimination and the development of suspiciousness symptoms in individuals at clinical high-risk for psychosis.

While individuals at clinical high-risk (CHR) for psychosis experience higher levels of discrimination than healthy controls, it is unclear how these experiences contribute to the etiology of attenuated positive symptoms. The present study examined the association of perceived discrimination with positive symptoms in a cohort from the North American Prodrome Longitudinal Study (NAPLS2). It predicted that CHR individuals will report higher levels of lifetime and past year perceived discrimination related to their race and ethnicity (ethnoracial discrimination) and that this form of discrimination will be significantly associated with baseline positive symptoms. Participants included 686 CHR and 252 healthy controls. The present study examined data from the perceived discrimination (PD) scale, the Brief Core Schema Scale, and the Scale for the Psychosis-Risk Symptoms. Structural equation modeling was employed to examine whether negative schema of self and others mediated the relation of past year ethnoracial PD to baseline suspiciousness symptoms. CHR individuals report higher levels of past year and lifetime PD compared to healthy controls. Lifetime ethnoracial PD was associated with suspiciousness and total positive symptoms. Negative schema of self and others scores partially mediated the relation of past year ethnoracial PD to suspiciousness, one of five positive symptom criteria for CHR. For CHR individuals, past year ethnoracial discrimination was associated with negative beliefs about themselves and others, which was associated with suspiciousness. These findings contribute to an emerging literature characterizing the mechanisms by which discrimination contributes to the positive symptoms characterizing the CHR syndrome.

Serum immune markers and transition to psychosis in individuals at clinical high risk

Individuals at clinical high risk (CHR) for psychosis have been found to have altered cytokine levels, but whether these changes are related to clinical outcomes remains unclear. We addressed this issue by measuring serum levels of 20 immune markers in 325 participants (n = 269 CHR, n = 56 healthy controls) using multiplex immunoassays, and then followed up the CHR sample to determine their clinical outcomes. Among 269 CHR individuals, 50 (18.6 %) developed psychosis by two years. Univariate and machine learning techniques were used to compare levels of inflammatory markers in CHR subjects and healthy controls, and in CHR subjects who had (CHR-t), or had not (CHR-nt) transitioned to psychosis.An ANCOVA identified significant group differences (CHR-t, CHR-nt and controls) and post-hoc tests indicated that VEGF levels and the IL-10/IL-6 ratio were significantly higher in CHR-t than CHR-nt, after adjusting for multiple comparisons. Using a penalised logistic regression classifier, CHR participants were distinguished from controls with an area-under the curve (AUC) of 0.82, with IL-6 and IL-4 levels the most important discriminating features. Transition to psychosis was predicted with an AUC of 0.57, with higher VEGF level and IL-10/IL-6 ratio the most important discriminating features. These data suggest that alterations in the levels of peripheral immune markers are associated with the subsequent onset of psychosis. The association with increased VEGF levels could reflect altered blood–brain-barrier (BBB) permeability, while the link with an elevated IL-10/IL-6 ratio points to an imbalance between anti- and pro-inflammatory cytokines.

Attentional biases in facial emotion processing in individuals at clinical high risk for psychosis.

Individuals at clinical high risk (CHR) for psychosis exhibit altered facial emotion processing (FEP) and poor social functioning. It is unclear whether FEP deficits result from attentional biases, and further, how these abnormalities are linked to symptomatology (e.g., negative symptoms) and highly comorbid disorders that are also tied to abnormal FEP (e.g., depression). In the present study, we employed an eye-tracking paradigm to assess attentional biases and clinical interviews to examine differences between CHR (N = 34) individuals and healthy controls (HC; N = 46), as well as how such biases relate to symptoms and functioning in CHR individuals. Although no CHR-HC differences emerged in attentional biases, within the CHR group, symptoms and functioning were related to biases. Depressive symptoms were related to some free-view attention switching biases (e.g., to and from fearful faces, r = .50). Negative symptoms were related to more slowly disengaging from happy faces (r = .44), spending less time looking at neutral faces (r = - .42), and more time looking at no face (Avolition, r = .44). In addition, global social functioning was related to processes that overlapped with both depression and negative symptoms, including time looking at no face (r = - .68) and free-view attention switching with fearful faces (r = - .40). These findings are consistent with previous research, indicating that negative symptoms play a prominent role in the CHR syndrome, with distinct mechanisms relative to depression. Furthermore, the results suggest that attentional bias indices from eye-tracking paradigms may be predictive of social functioning.

Multivariate joint models for the dynamic prediction of psychosis in individuals with clinical high risk

This study attempted to construct and validate dynamic prediction via multivariate joint models and compare the prognostic performance of these models to both static and univariate joint models. Individuals with clinical high risk(CHR)(n=289) were recruited and re-assessed for positive symptoms, general functions, and conversion to psychosis at 2-months, 1-year, and 2-years to develop the dynamic models. A multivariate joint model of positive psychotic symptoms was assessed using the Structured Interview for Prodromal Symptoms(SIPSp) and general function assessed by global assessment of functioning scores(GAFs) with time-to-conversion to psychosis. The area under the receiver operating characteristic(ROC) curve(AUC) was used to test the accuracy of the models. Among 298 CHR individuals, 68 converted to psychosis within 2 years after the initial assessments. Multivariate joint models showed that declining GAFs and increasing SIPSp corresponded to significant and trending to significantly increased risk of psychosis onset and had much higher prognostic accuracy (cross-validated AUC=0.9) compared to the static model(AUC=0.6) and univariate joint models(cross-validated AUC=0.6-0.8). Our results showed that multivariate joint models could be highly efficient in forecasting psychosis onset for CHR individuals. Longitudinal assessments for psychopathology and general functions can be useful for dynamically predicting the prognosis of the pre-morbid phase of psychosis.

Using automatic acoustic analysis to reveal disruptions to speech articulation in individuals at risk for psychosis

Individuals who are experiencing attenuated psychosis symptoms (placing them at clinical high risk for developing psychosis) exhibit disruptions to cortico-cerebellar circuits that manifest as difficulties in motor control of the face and limbs. These motor dysfunctions are predictive of the onset and progression of psychosis, making them a potential biomarker for this devastating disease. We examine whether these motor abnormalities disrupt speech production, leading to greater variability in speech acoustics. Clinical high risk (CHR) individuals and matched healthy control (HC) individuals produced diadochokinetic speech (rapid, repeated syllable production, e.g., papapa…, pataka…) and read aloud a paragraph. Consonant and vowel onsets and offsets were automatically segmented from diadochokinetic speech using a deep-learning model trained on human annotators. Read speech was automatically segmented at the word level using forced alignment. Vowel segmentation from read speech was based on forced aligner output; stop consonant onset/offsets were segmented by a deep-learning model. The segmentations from each task were then used to estimate speech rate, voice onset time (VOT), vowel durations and formant trajectories. CHR individuals produced more variable VOTs and exhibited greater speech rate variability than HC individuals in both tasks. This suggests that speech acoustics may provide a window into disruptions in this at-risk population.