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.

Immersive virtual reality in the treatment of auditory hallucinations: A PRISMA scoping review.

BACKGROUND: A large group of psychiatric patients suffer from auditory hallucinations (AH) despite relevant treatment regimens. In mental health populations, AH tend to be verbal (AVH) and the content critical or abusive. Trials employing immersive virtual reality (VR) to treat mental health disorders are emerging. OBJECTIVE: The aim of this scoping review is to provide an overview of clinical trials utilizing VR in the treatment of AH and to document knowledge gaps in the literature. METHODS: PubMed, Cochrane Library, and Embase were searched for studies reporting on the use of VR to target AH. RESULTS: 16 papers were included in this PRISMA scoping review (ScR). In most studies VR therapy (VRT) was employed to ameliorate treatment resistant AVH in schizophrenia spectrum disorders. Only two studies included patients with a diagnosis of affective disorders. The VRT was carried out with the use of an avatar to represent the patient's most dominant voice. DISCUSSION: The research field employing VR to treat AH is promising but still in its infancy. Results from larger randomized clinical trials are needed to establish substantial evidence of therapy effectiveness. Additionally, the knowledge base would benefit from more profound qualitative data exploring views of patients and therapists.

20-year neurocognitive development following a schizophrenia spectrum disorder and associations with symptom severity and functional outcomes.

BACKGROUND: Cognitive deficits are a core feature of schizophrenia and are closely associated with poor functional outcomes. It remains unclear if cognitive deficits progress over time or remain stable. Determining patients at increased risk of progressive worsening might help targeted neurocognitive remediation approaches. METHODS: This 20-year follow-up study examined neurocognitive outcomes of 156 participants from the OPUS I trial. Neurocognition was assessed using the brief assessment of cognition in schizophrenia at the 10- and 20-year follow-up, allowing us to examine changes in neurocognition over ten years. RESULTS: We found that 30.5% of patients had a declining course of neurocognition, 49.2% had a stable course of neurocognition and 20.3% experienced improvements in neurocognition. Good cognitive functioning at the 20-year follow-up was significantly associated with higher levels of social functioning (B 6.86, CI 4.71-9.02, p < 0.001) while increasing experiential negative symptoms were significantly correlated to cognitive worsening (PC-0.231, p = 0.029). Younger age at inclusion (B: 0.23 per 10-years, CI 0.00-0.045, p = 0.047) and low level of education (below ten years) (mean difference: -0.346, CI -0.616 to -0.076, p = 0.012) predicted declining neurocognition. CONCLUSION: Our findings support the notion of different schizophrenia subtypes with varying trajectories. Neurocognitive impairment at the 20-year follow-up was associated with other poor outcomes, highlighting the importance of treatments aimed at improving neurocognition in patients with schizophrenia spectrum disorders.

Using brain structural neuroimaging measures to predict psychosis onset for individuals at clinical high-risk.

Machine learning approaches using structural magnetic resonance imaging (sMRI) can be informative for disease classification, although their ability to predict psychosis is largely unknown. We created a model with individuals at CHR who developed psychosis later (CHR-PS+) from healthy controls (HCs) that can differentiate each other. We also evaluated whether we could distinguish CHR-PS+ individuals from those who did not develop psychosis later (CHR-PS-) and those with uncertain follow-up status (CHR-UNK). T1-weighted structural brain MRI scans from 1165 individuals at CHR (CHR-PS+, n = 144; CHR-PS-, n = 793; and CHR-UNK, n = 228), and 1029 HCs, were obtained from 21 sites. We used ComBat to harmonize measures of subcortical volume, cortical thickness and surface area data and corrected for non-linear effects of age and sex using a general additive model. CHR-PS+ (n = 120) and HC (n = 799) data from 20 sites served as a training dataset, which we used to build a classifier. The remaining samples were used external validation datasets to evaluate classifier performance (test, independent confirmatory, and independent group [CHR-PS- and CHR-UNK] datasets). The accuracy of the classifier on the training and independent confirmatory datasets was 85% and 73% respectively. Regional cortical surface area measures-including those from the right superior frontal, right superior temporal, and bilateral insular cortices strongly contributed to classifying CHR-PS+ from HC. CHR-PS- and CHR-UNK individuals were more likely to be classified as HC compared to CHR-PS+ (classification rate to HC: CHR-PS+, 30%; CHR-PS-, 73%; CHR-UNK, 80%). We used multisite sMRI to train a classifier to predict psychosis onset in CHR individuals, and it showed promise predicting CHR-PS+ in an independent sample. The results suggest that when considering adolescent brain development, baseline MRI scans for CHR individuals may be helpful to identify their prognosis. Future prospective studies are required about whether the classifier could be actually helpful in the clinical settings.

Study protocol for RUFUS-A randomized mixed methods pilot clinical trial investigating the relevance and feasibility of rumination-focused cognitive behavioral therapy in the treatment of patients with emergent psychosis spectrum disorders.

INTRODUCTION: Psychosis spectrum disorders are characterized by both positive and negative symptoms, but whereas there is good effect of treatment on positive symptoms, there is still a scarcity of effective interventions aimed at reducing negative symptoms. Rumination has been proposed as an important and fundamental factor in the development and maintenance of symptoms across psychiatric diagnoses, and there is a need to develop effective interventions targeting rumination behaviors and negative symptoms in patients with psychotic disorders. The aim of the current study is to investigate the feasibility and acceptability of group rumination-focused cognitive behavioral therapy (RFCBT) in the treatment of young people with psychosis spectrum disorders as well as investigating potential indications of treatment efficacy. METHODS AND ANALYSIS: The study is a mixed-method clinical randomized controlled pilot trial with a target sample of 60 patients, who are randomized to either receive 13 weeks of group RFCBT or 13 weeks of treatment as usual (TAU). All patients are examined at the start of the project and at the 13-week follow-up. We will compare changes in outcomes from baseline to posttreatment between group RFCBT and TAU. In addition, qualitative analyzes are carried out to explore feasibility and acceptability and to uncover the patients' experience of receiving the intervention.

Development of the PSYCHS: Positive SYmptoms and Diagnostic Criteria for the CAARMS Harmonized with the SIPS.

AIM: To harmonize two ascertainment and severity rating instruments commonly used for the clinical high risk syndrome for psychosis (CHR-P): the Structured Interview for Psychosis-risk Syndromes (SIPS) and the Comprehensive Assessment of At-Risk Mental States (CAARMS). METHODS: The initial workshop is described in the companion report from Addington et al. After the workshop, lead experts for each instrument continued harmonizing attenuated positive symptoms and criteria for psychosis and CHR-P through an intensive series of joint videoconferences. RESULTS: Full harmonization was achieved for attenuated positive symptom ratings and psychosis criteria, and modest harmonization for CHR-P criteria. The semi-structured interview, named Positive SYmptoms and Diagnostic Criteria for the CAARMS Harmonized with the SIPS (PSYCHS), generates CHR-P criteria and severity scores for both CAARMS and SIPS. CONCLUSIONS: Using the PSYCHS for CHR-P ascertainment, conversion determination, and attenuated positive symptom severity rating will help in comparing findings across studies and in meta-analyses.

Normative Modeling of Brain Morphometry in Clinical High Risk for Psychosis.

Importance: The lack of robust neuroanatomical markers of psychosis risk has been traditionally attributed to heterogeneity. A complementary hypothesis is that variation in neuroanatomical measures in individuals at psychosis risk may be nested within the range observed in healthy individuals. Objective: To quantify deviations from the normative range of neuroanatomical variation in individuals at clinical high risk for psychosis (CHR-P) and evaluate their overlap with healthy variation and their association with positive symptoms, cognition, and conversion to a psychotic disorder. Design, Setting, and Participants: This case-control study used clinical-, IQ-, and neuroimaging software (FreeSurfer)-derived regional measures of cortical thickness (CT), cortical surface area (SA), and subcortical volume (SV) from 1340 individuals with CHR-P and 1237 healthy individuals pooled from 29 international sites participating in the Enhancing Neuroimaging Genetics Through Meta-analysis (ENIGMA) Clinical High Risk for Psychosis Working Group. Healthy individuals and individuals with CHR-P were matched on age and sex within each recruitment site. Data were analyzed between September 1, 2021, and November 30, 2022. Main Outcomes and Measures: For each regional morphometric measure, deviation scores were computed as z scores indexing the degree of deviation from their normative means from a healthy reference population. Average deviation scores (ADS) were also calculated for regional CT, SA, and SV measures and globally across all measures. Regression analyses quantified the association of deviation scores with clinical severity and cognition, and 2-proportion z tests identified case-control differences in the proportion of individuals with infranormal (z < -1.96) or supranormal (z > 1.96) scores. Results: Among 1340 individuals with CHR-P, 709 (52.91%) were male, and the mean (SD) age was 20.75 (4.74) years. Among 1237 healthy individuals, 684 (55.30%) were male, and the mean (SD) age was 22.32 (4.95) years. Individuals with CHR-P and healthy individuals overlapped in the distributions of the observed values, regional z scores, and all ADS values. For any given region, the proportion of individuals with CHR-P who had infranormal or supranormal values was low (up to 153 individuals [<11.42%]) and similar to that of healthy individuals (<115 individuals [<9.30%]). Individuals with CHR-P who converted to a psychotic disorder had a higher percentage of infranormal values in temporal regions compared with those who did not convert (7.01% vs 1.38%) and healthy individuals (5.10% vs 0.89%). In the CHR-P group, only the ADS SA was associated with positive symptoms (ß = -0.08; 95% CI, -0.13 to -0.02; P = .02 for false discovery rate) and IQ (ß = 0.09; 95% CI, 0.02-0.15; P = .02 for false discovery rate). Conclusions and Relevance: In this case-control study, findings suggest that macroscale neuromorphometric measures may not provide an adequate explanation of psychosis risk.

Treatment of schizotypal disorder: a protocol for a systematic review of the evidence and recommendations for clinical practice.

INTRODUCTION: Schizotypal disorder is associated with a high level of disability at an individual level and high societal costs. However, clinical recommendations for the treatment of schizotypal disorder are scarce and based on limited evidence. This review aims to synthesise the current evidence on treatment for schizotypal disorder making recommendations for clinical practice. METHODS AND ANALYSIS: This systematic review protocol follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A systematic literature search will be performed in PsychArticles, Embase, Medline and Cochrane Central Register of Controlled Trials. Additionally, we will search for relevant articles manually. Inclusion criteria are published studies including individuals diagnosed with schizotypal personality disorder according to Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria, or schizotypal disorder according to International Classification of Diseases (ICD) criteria. We will include interventional studies comprising any pharmacological and non-pharmacological treatment trials for patients with schizotypal disorder, and all relevant outcome measures will be reported. Risk of bias will be assessed by Cochrane risk-of-bias tools. Data will be synthesised using narrative or thematic analysis and, if suitable, through meta-analysis. ETHICS AND DISSEMINATION: No original data will be collected as part of this study and ethics approval is, therefore, not applicable. The results will be disseminated through peer-reviewed publication and presented at international scientific meetings. We will aim at submitting the final paper for publication within 4 months of completion of analyses. Furthermore, this systematic review will inform clinicians and researchers on the current state of evidence on treatment for schizotypal disorder. Findings may guide proposals for further research and potentially guide recommendations for clinical practice using the Grading of Recommendations Assessment, Development and Evaluation. PROSPERO REGISTRATION NUMBER: CRD42022375001.

Study protocol for virtual leisure investigating the effect of virtual reality-delivered stress reduction, entertainment and distraction on the use of coercion and need-based medication and patient satisfaction at a closed psychiatric intensive care unit - a mixed-methods pilot clinical trial.

INTRODUCTION: The environment at a psychiatric inpatient ward can lead to emotional distress and behavioural deviations in vulnerable individuals potentially resulting in conflicts, increased use of need-based medication and coercive actions, along with low satisfaction with treatment. To accommodate these challenges, recreational and entertaining interventions are recommended. The tested interventions have, however, shown varying effects and demand a high degree of planning and staff involvement while being difficult to adapt to individual needs. Virtual reality (VR) may help overcome these challenges. METHODS AND ANALYSIS: The study is a mixed-methods clinical trial with a target sample of 124 patients hospitalised at a closed psychiatric ward in the capital region of Denmark. Outcomes (eg, coercion, need-based medication and perceived stress) for a 12-month period where all patients are offered VR-based recreational experiences during their hospitalisation will be compared with outcomes for a 12-month period where VR is not offered. Feasibility and acceptability will be explored with qualitative interviews supplemented with non-participant observations and focus groups. The study began on 1 January 2023, and we expect to complete data collection by 31 December 2024. ETHICS AND DISSEMINATION: The study is registered at Danish Data Protection Agency (j.no P-2022-466) and is approved by the Committee on Health Research Ethics of the capital region of Denmark (j.no 22013313). All patients will be required to provide informed consent. Results from this study will be disseminated via peer-reviewed journals and congress/consortium presentations. TRIAL REGISTRATION NUMBER: NCT05654740.

Examination of gaze behaviour in social anxiety disorder using a virtual reality eye-tracking paradigm: protocol for a case-control study.

INTRODUCTION: Social anxiety disorder (SAD) has an early onset, a high lifetime prevalence, and may be a risk factor for developing other mental disorders. Gaze behaviour is considered an aberrant feature of SAD. Eye-tracking, a novel technology device, enables recording eye movements in real time, making it a direct and objective measure of gaze behaviour. Virtual reality (VR) is a promising tool for assessment and diagnostic purposes. Developing an objective screening tool based on examination of gaze behaviour in SAD may potentially aid early detection. The objective of this current study is, therefore to examine gaze behaviour in SAD utilising VR. METHODS AND ANALYSIS: A case-control study design is employed in which a clinical sample of 29 individuals with SAD will be compared with a matched healthy control group of 29 individuals. In the VR-based eye-tracking paradigm, participants will be presented to stimuli consisting of high-res 360° 3D stereoscopic videos of three social-evaluative tasks designed to elicit social anxiety. The study will investigate between-group gaze behaviour differences during stimuli presentation. ETHICS AND DISSEMINATION: The study has been approved by the National Committee on Health Research Ethics for the Capital Region of Denmark (H-22041443). The study has been preregistered on OSF registries: https://doi.org/10.17605/OSF.IO/XCTAKAll participants will be provided with written and oral information. Informed consent is required for all the participants. Participation is voluntarily, and the participants can at any time terminate their participation without any consequences. Study results; positive, negative or inconclusive will be published in relevant scientific journals.

Associations between saliva alpha-amylase, heart rate variability, saliva cortisol and cognitive performance in individuals at ultra high-risk for psychosis.

BACKGROUND: Cognitive impairments are present in individuals at ultra-high risk (UHR) of psychosis and UHR individuals exhibit a hyperactive and dysfunctional HPA-axis. Increasing stress levels could potentially lead to cognitive impairments and no previous studies have examined the association between physiological stress biomarkers and cognition in UHR individuals. This study aims to examine the association between saliva alpha amylase (SAA), heart rate variability (HRV), saliva cortisol, and cognition in UHR individuals. METHOD: We included 72 UHR individuals, aged 18-40, fulfilling criteria of the comprehensive assessment of at-risk mental state (CAARMS). Cognitive tests indexed the 7 core domains as stated by Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS). Physiological stress levels were observed for one day: saliva was collected at awakening, 30 min and 60 min after awakening and at bedtime. HRV was measured during sleep and before awakening. We used generalized linear model and controlled for multiple testing using false discovery rate (FDR). RESULTS: Higher levels of SAA were significantly associated with lower cognitive performance in the domains of verbal and visual learning and memory, sustained attention, working memory and global neurocognition looking at unadjusted data. Controlling for FDR visual memory, sustained attention and global neurocognition remained significant associated with SAA. We discovered no associations between cortisol and cognition. CONCLUSION: Visual learning and memory, sustained attention and global neurocognition remained significantly associated with SAA. This finding supports our hypothesis that an association between abnormal stress biomarkers and impaired cognition might be present in UHR individuals.

A longitudinal study on physiological stress in individuals at ultra high-risk of psychosis.

INTRODUCTION: Individuals at ultra high-risk (UHR) of psychosis exhibit significantly higher stress levels than healthy controls (HC). This study investigates how physiological stress measures differ between HC and UHR individuals and how physiological stress is associated with attenuated psychotic symptoms and changes over time in UHR individuals. Additionally, it examines how the use of medication affects physiological levels of stress. METHOD: The study included 72 UHR individuals and 36 HC. UHR were included according to the comprehensive assessment of at-risk mental state (CAARMS); a total-CAARMS score measured the attenuated psychotic symptoms and was calculated from the four psychosis subscales. HC and UHR were examined at baseline, and 47 UHR individuals were followed up after six months. Physiological stress measures were salivary cortisol, alpha-amylase (SAA) and heart-rate variability (HRV). Saliva was collected at four-time points during the day. RESULTS: There was no significant difference regarding cortisol (awakening response) or SAA measures between HC and UHR individuals. The use of antipsychotics and antidepressants was associated with low HRV in UHR individuals. In an exploratory analysis of 19 UHR individuals, we found an association between the change in total-CAARMS (six months total-CAARMS minus baseline total CAARMS) and the change in HRV during sleep (six months HRV minus baseline HRV). CONCLUSION: Our findings indicate that the use of antipsychotics and antidepressants could be associated with lower HRV in UHR individuals. There might be potential to investigate how HRV develops during the course of illness in UHR individuals.

Normative modeling of brain morphometry in Clinical High-Risk for Psychosis.

Importance: The lack of robust neuroanatomical markers of psychosis risk has been traditionally attributed to heterogeneity. A complementary hypothesis is that variation in neuroanatomical measures in the majority of individuals at psychosis risk may be nested within the range observed in healthy individuals. Objective: To quantify deviations from the normative range of neuroanatomical variation in individuals at clinical high-risk for psychosis (CHR-P) and evaluate their overlap with healthy variation and their association with positive symptoms, cognition, and conversion to a psychotic disorder. Design Setting and Participants: Clinical, IQ and FreeSurfer-derived regional measures of cortical thickness (CT), cortical surface area (SA), and subcortical volume (SV) from 1,340 CHR-P individuals [47.09% female; mean age: 20.75 (4.74) years] and 1,237 healthy individuals [44.70% female; mean age: 22.32 (4.95) years] from 29 international sites participating in the ENIGMA Clinical High Risk for Psychosis Working Group. Main Outcomes and Measures: For each regional morphometric measure, z-scores were computed that index the degree of deviation from the normative means of that measure in a healthy reference population (N=37,407). Average deviation scores (ADS) for CT, SA, SV, and globally across all measures (G) were generated by averaging the respective regional z-scores. Regression analyses were used to quantify the association of deviation scores with clinical severity and cognition and two-proportion z-tests to identify case-control differences in the proportion of individuals with infranormal (z<-1.96) or supranormal (z>1.96) scores. Results: CHR-P and healthy individuals overlapped in the distributions of the observed values, regional z-scores, and all ADS vales. The proportion of CHR-P individuals with infranormal or supranormal values in any metric was low (<12%) and similar to that of healthy individuals. CHR-P individuals who converted to psychosis compared to those who did not convert had a higher percentage of infranormal values in temporal regions (5-7% vs 0.9-1.4%). In the CHR-P group, only the ADSSA showed significant but weak associations (|ß|<0.09; PFDR<0.05) with positive symptoms and IQ. Conclusions and Relevance: The study findings challenge the usefulness of macroscale neuromorphometric measures as diagnostic biomarkers of psychosis risk and suggest that such measures do not provide an adequate explanation for psychosis risk.

Premorbid functioning in adolescence associates with comorbid disorders in individuals at ultra-high risk for psychosis: A brief report.

AIM: This study examines associations between premorbid adjustment and comorbid disorders in individuals at ultra-high risk (UHR) for psychosis. METHODS: Premorbid social and academic adjustment data were collected from 146 UHR individuals using the Premorbid Adjustment Scale. Comorbid disorders were determined by the Structural Clinical Interview for DSM-IV. RESULTS: Logistic regressions showed lower premorbid social adjustment associated with personality disorders. Lower premorbid academic adjustment associated with affective disorders. More specifically, poor premorbid social adjustment in early and late adolescence associated with personality disorders. Lower premorbid social adjustment in late adolescence and lower premorbid academic adjustment in early adolescence associated with affective disorders. CONCLUSION: Partly corroborating evidence from schizophrenia samples, our findings suggest that poor premorbid adjustment relate to distinct comorbid disorders in UHR individuals. If replicated, it indicates that premorbid adjustment deficits may be a key area for targeted interventions improving the clinical prognosis of UHR individuals.

Sleep disturbances and the association with attenuated psychotic symptoms in individuals at ultra high-risk of psychosis.

Sleep disturbances are common in individuals at ultra high-risk (UHR) of psychosis and have proven to play a causal role in the occurrence of psychotic symptoms in healthy individuals. Only a few studies have systematically investigated sleep disturbances in UHR individuals. The help-seeking UHR individuals were 18-40 years old, and we included 72 UHR individuals according to the Comprehensive Assessment of At-Risk Mental State criteria (CAARMS) and 36 healthy controls. Sleep was measured with a modified version of the Karolinska Sleep Questionnaire and actigraphy for one night, and melatonin was measured at awakening and bedtime. We compared subjective rated sleep and actigraphy between healthy and UHR individuals (t-test and chi-square test) and examined the association between a CAARMS-composite score (linear regression). UHR individuals subjectively experienced poor sleep, categorised as disturbed sleep- and awakening index compared with healthy controls. We found no differences in actigraphy variables or morning/evening melatonin between UHR and healthy controls (t-test and chi-square). A high CAARMS-composite score was associated with high morning melatonin (B = 0.15, CI 0.02 to 0.27, p = 0.024) and high awakening index (B = 1.86, CI 0.58 to 3.14, p = 0.004) in UHR individuals. The results suggest that UHR individuals with high CAARMS scores have a delayed sleep phase; they have difficulties waking up and feel exhausted at awakening. It might be necessary to evaluate how UHR individuals sleep, and it would be of great interest to follow these patients over time according to the development of psychosis.

Premorbid adjustment associates with cognitive and functional deficits in individuals at ultra-high risk of psychosis.

Premorbid social and academic adjustment are important predictors of cognitive and functional performance in schizophrenia. Whether this relationship is also present in individuals at ultra-high risk (UHR) for psychosis is the focus of the present study. Using baseline data from a randomised clinical trial (N = 146) this study investigated associations between premorbid adjustment and neuro- and social cognition and functioning in UHR individuals aged 18-40 years. Patients were evaluated with the Premorbid Adjustment Scale (PAS) comprising a social and an academic domain. Using validated measures neurocognition was assessed in the domains of processing speed, executive function, attention, verbal learning and memory, visual learning and memory, and working memory along with estimated IQ. Social cognitive domains assessed were theory of mind, emotion recognition, and attributional bias. Functional assessment comprised the domains of social- and role functioning, functional capacity, and quality of life. Linear regression analyses revealed poor premorbid academic adjustment to be associated with poorer performance in processing speed, working memory, attention, full scale IQ, and verbal IQ. Poor premorbid social adjustment was associated with theory of mind deficits. Additionally, both premorbid adjustment domains were associated with social- and role functioning and quality of life. Corroborating evidence from schizophrenia samples, our findings indicate poor premorbid adjustment to correlate with deficits in specific cognitive and functional domains in UHR states. Early premorbid adjustment difficulties may therefore indicate a poor cognitive and functional trajectory associated with significant impairments in early and established psychotic disorders suggesting targets for primary intervention.

Neuroanatomical heterogeneity and homogeneity in individuals at clinical high risk for psychosis.

Individuals at Clinical High Risk for Psychosis (CHR-P) demonstrate heterogeneity in clinical profiles and outcome features. However, the extent of neuroanatomical heterogeneity in the CHR-P state is largely undetermined. We aimed to quantify the neuroanatomical heterogeneity in structural magnetic resonance imaging measures of cortical surface area (SA), cortical thickness (CT), subcortical volume (SV), and intracranial volume (ICV) in CHR-P individuals compared with healthy controls (HC), and in relation to subsequent transition to a first episode of psychosis. The ENIGMA CHR-P consortium applied a harmonised analysis to neuroimaging data across 29 international sites, including 1579 CHR-P individuals and 1243 HC, offering the largest pooled CHR-P neuroimaging dataset to date. Regional heterogeneity was indexed with the Variability Ratio (VR) and Coefficient of Variation (CV) ratio applied at the group level. Personalised estimates of heterogeneity of SA, CT and SV brain profiles were indexed with the novel Person-Based Similarity Index (PBSI), with two complementary applications. First, to assess the extent of within-diagnosis similarity or divergence of neuroanatomical profiles between individuals. Second, using a normative modelling approach, to assess the 'normativeness' of neuroanatomical profiles in individuals at CHR-P. CHR-P individuals demonstrated no greater regional heterogeneity after applying FDR corrections. However, PBSI scores indicated significantly greater neuroanatomical divergence in global SA, CT and SV profiles in CHR-P individuals compared with HC. Normative PBSI analysis identified 11 CHR-P individuals (0.70%) with marked deviation (>1.5 SD) in SA, 118 (7.47%) in CT and 161 (10.20%) in SV. Psychosis transition was not significantly associated with any measure of heterogeneity. Overall, our examination of neuroanatomical heterogeneity within the CHR-P state indicated greater divergence in neuroanatomical profiles at an individual level, irrespective of psychosis conversion. Further large-scale investigations are required of those who demonstrate marked deviation.

Association of Structural Magnetic Resonance Imaging Measures With Psychosis Onset in Individuals at Clinical High Risk for Developing Psychosis: An ENIGMA Working Group Mega-analysis.

Importance: The ENIGMA clinical high risk (CHR) for psychosis initiative, the largest pooled neuroimaging sample of individuals at CHR to date, aims to discover robust neurobiological markers of psychosis risk. Objective: To investigate baseline structural neuroimaging differences between individuals at CHR and healthy controls as well as between participants at CHR who later developed a psychotic disorder (CHR-PS+) and those who did not (CHR-PS-). Design, Setting, and Participants: In this case-control study, baseline T1-weighted magnetic resonance imaging (MRI) data were pooled from 31 international sites participating in the ENIGMA Clinical High Risk for Psychosis Working Group. CHR status was assessed using the Comprehensive Assessment of At-Risk Mental States or Structured Interview for Prodromal Syndromes. MRI scans were processed using harmonized protocols and analyzed within a mega-analysis and meta-analysis framework from January to October 2020. Main Outcomes and Measures: Measures of regional cortical thickness (CT), surface area, and subcortical volumes were extracted from T1-weighted MRI scans. Independent variables were group (CHR group vs control group) and conversion status (CHR-PS+ group vs CHR-PS- group vs control group). Results: Of the 3169 included participants, 1428 (45.1%) were female, and the mean (SD; range) age was 21.1 (4.9; 9.5-39.9) years. This study included 1792 individuals at CHR and 1377 healthy controls. Using longitudinal clinical information, 253 in the CHR-PS+ group, 1234 in the CHR-PS- group, and 305 at CHR without follow-up data were identified. Compared with healthy controls, individuals at CHR exhibited widespread lower CT measures (mean [range] Cohen d = -0.13 [-0.17 to -0.09]), but not surface area or subcortical volume. Lower CT measures in the fusiform, superior temporal, and paracentral regions were associated with psychosis conversion (mean Cohen d = -0.22; 95% CI, -0.35 to 0.10). Among healthy controls, compared with those in the CHR-PS+ group, age showed a stronger negative association with left fusiform CT measures (F = 9.8; P < .001; q < .001) and left paracentral CT measures (F = 5.9; P = .005; q = .02). Effect sizes representing lower CT associated with psychosis conversion resembled patterns of CT differences observed in ENIGMA studies of schizophrenia (ρ = 0.35; 95% CI, 0.12 to 0.55; P = .004) and individuals with 22q11.2 microdeletion syndrome and a psychotic disorder diagnosis (ρ = 0.43; 95% CI, 0.20 to 0.61; P = .001). Conclusions and Relevance: This study provides evidence for widespread subtle, lower CT measures in individuals at CHR. The pattern of CT measure differences in those in the CHR-PS+ group was similar to those reported in other large-scale investigations of psychosis. Additionally, a subset of these regions displayed abnormal age associations. Widespread disruptions in CT coupled with abnormal age associations in those at CHR may point to disruptions in postnatal brain developmental processes.

Self-perceived cognitive impairments in psychosis ultra-high risk individuals: associations with objective cognitive deficits and functioning.

There is a scarcity of evidence on subjectively reported cognitive difficulties in individuals at ultra-high risk (UHR) for psychosis and whether these self-perceived cognitive difficulties may relate to objective cognitive deficits, psychopathology, functioning, and adherence to cognitive remediation (CR). Secondary, exploratory analyses to a randomized, clinical trial were conducted with 52 UHR individuals receiving a CR intervention. Participants completed the Measure of Insight into Cognition-Self Report (MIC-SR), a measure of daily life cognitive difficulties within the domains of attention, memory, and executive functions along with measures of neuropsychological test performance, psychopathology, functioning, and quality of life. Our study found participants with and without objectively defined cognitive deficits reported self-perceived cognitive deficits of the same magnitude. No significant relationship was revealed between self-perceived and objectively measured neurocognitive deficits. Self-perceived cognitive deficits associated with attenuated psychotic symptoms, overall functioning, and quality of life, but not with adherence to, or neurocognitive benefits from, a CR intervention. Our findings indicate that UHR individuals may overestimate their cognitive difficulties, and higher levels of self-perceived cognitive deficits may relate to poor functioning. If replicated, this warrants a need for both subjective and objective cognitive assessment in at-risk populations as this may guide psychoeducational approaches and pro-functional interventions. Self-perceived cognitive impairments do not seem to directly influence CR adherence and outcome in UHR states. Further studies are needed on potential mediator between self-perceived cognitive deficits and functioning and quality of life.

Cerebral Glutamate and Gamma-Aminobutyric Acid Levels in Individuals at Ultra-high Risk for Psychosis and the Association With Clinical Symptoms and Cognition.

BACKGROUND: Studies examining glutamate or gamma-aminobutyric acid (GABA) in ultra-high risk for psychosis (UHR) and the association with pathophysiology and cognition have shown conflicting results. We aimed to determine whether perturbed glutamate and GABA levels in the anterior cingulate cortex and glutamate levels in the left thalamus were present in UHR individuals and to investigate associations between metabolite levels and clinical symptoms and cognition. METHODS: We included 122 UHR individuals and 60 healthy control subjects. Participants underwent proton magnetic resonance spectroscopy to estimate glutamate and GABA levels and undertook clinical and cognitive assessments. RESULTS: We found no differences in metabolite levels between UHR individuals and healthy control subjects. In UHR individuals, we found negative correlations in the anterior cingulate cortex between the composite of glutamate and glutamine (Glx) and the Comprehensive Assessment of At-Risk Mental States composite score (p = .04) and between GABA and alogia (p = .01); positive associations in the anterior cingulate cortex between glutamate (p = .01) and Glx (p = .01) and spatial working memory and between glutamate (p = .04), Glx (p = .04), and GABA (p = .02) and set-shifting; and a positive association in the thalamus between glutamate and attention (p = .04). No associations between metabolites and clinical or cognitive scores were found in the healthy control subjects. CONCLUSIONS: An association between glutamate and GABA levels and clinical symptoms and cognition found only in UHR individuals suggests a loss of the normal relationship between metabolite levels and cognitive function. Longitudinal studies with investigation of clinical and cognitive outcome and the association with baseline levels of glutamate and GABA could illuminate whether glutamatergic and GABAergic dysfunction predicts clinical outcome.