The association between migrant status and transition in an ultra-high risk for psychosis population.

PURPOSE: Migrant status is one of the most replicated and robust risk factors for developing a psychotic disorder. This study aimed to determine whether migrant status in people identified as Ultra-High Risk for Psychosis (UHR) was associated with risk of transitioning to a full-threshold psychotic disorder. METHODS: Hazard ratios for the risk of transition were calculated from five large UHR cohorts (n = 2166) and were used to conduct a meta-analysis using the generic inverse-variance method using a random-effects model. RESULTS: 2166 UHR young people, with a mean age of 19.1 years (SD ± 4.5) were included, of whom 221 (10.7%) were first-generation migrants. A total of 357 young people transitioned to psychosis over a median follow-up time of 417 days (I.Q.R.147-756 days), representing 17.0% of the cohort. The risk of transition to a full-threshold disorder was not increased for first-generation migrants, (HR = 1.08, 95% CI 0.62-1.89); however, there was a high level of heterogeneity between studies The hazard ratio for second-generation migrants to transition to a full-threshold psychotic disorder compared to the remainder of the native-born population was 1.03 (95% CI 0.70-1.51). CONCLUSIONS: This meta-analysis did not find a statistically significant association between migrant status and an increased risk for transition to a full-threshold psychotic disorder; however, several methodological issues could explain this finding. Further research should focus on examining the risk of specific migrant groups and also ensuring that migrant populations are adequately represented within UHR clinics.

Opening the Black Box of Cognitive-Behavioural Case Management in Clients with Ultra-High Risk for Psychosis.

BACKGROUND: Cognitive-behavioural therapy (CBT) is the first-choice treatment in clients with ultra-high risk (UHR) for psychosis. However, CBT is an umbrella term for a plethora of different strategies, and little is known about the association between the intensity and content of CBT and the severity of symptomatic outcome. METHODS: A sample of 268 UHR participants received 6 months of CBT with case management (CBCM) in the context of the multi-centre NEURAPRO trial with monthly assessments of attenuated psychotic symptoms (APS). Using multilevel regressions and controlling for the initial severity of APS, the associations between (1) number of CBCM sessions received and severity of APS and (2) specific CBCM components and severity of APS were investigated. RESULTS: In month 1, a higher number of sessions and more assessment of symptoms predicted an increase in APS, while in month 3, a higher number of sessions and more monitoring predicted a decrease in the level of APS. More therapeutic focus on APS predicted an overall increase in APS. CONCLUSIONS: Our findings indicate that the association between intensity/content of CBCM and severity of APS in a sample of UHR participants depends on the length of time in treatment. CBCM may positively impact the severity of APS later in the course of treatment. Therefore, it would seem important to keep UHR young people engaged in treatment beyond this initial period. Regarding the specific content of CBCM, a therapeutic focus on APS may not necessarily be beneficial in reducing the severity of APS, a possibility in need of further investigation.

The development of a randomised controlled trial testing the effects of an online intervention among school students at risk of suicide.

BACKGROUND: Suicide-related behaviour among young people is of significant concern, yet little is known regarding the effectiveness of interventions designed to reduce risk among this population. Of those interventions that have been tested, cognitive-behavioural therapy appears to show some promise among young people with suicidal ideation. Internet-based interventions are becoming increasingly popular and have shown some effect in preventing and treating depression and anxiety in young people. However, to date there are no randomised controlled trials examining the impact of Internet-based Cognitive Behavioural Therapy among suicidal youth. METHODS/DESIGN: This is a randomised controlled trial testing the effects of Internet-based cognitive-behavioural therapy among suicidal high school students who have sought help from the school wellbeing team. The intervention comprises 8 modules of Cognitive Behavioural Therapy delivered online. The study has a staggered, two-year recruitment phase and participants are assessed at baseline, post intervention and 12 weeks later. DISCUSSION: If effective the program has the ability to be readily adapted and delivered to a range of populations in a range of settings, at relatively little cost. It can also be adapted for mobile applications. TRIAL REGISTRATION: ACTRN12613000864729. Date registered: 05/08/2013.

Transdiagnostic risk identification: A validation study of the Clinical High At Risk Mental State (CHARMS) criteria.

A set of clinical criteria, the Clinical High At-Risk Mental State (CHARMS) criteria, have been developed to identify symptomatic young people who are at-risk of disorder progression. The current study aimed to validate the CHARMS criteria by testing whether they prospectively identify individuals at-risk of progressing from attenuated symptomatology to a first episode of serious mental disorder, namely first episode psychosis, first episode mania, severe major depression, and borderline personality disorder. 121 young people completed clinical evaluations at baseline, 6- and 12-month follow-up. The Kaplan-Meier method was used to assess transition rates. Cox regression and LASSO were used to examine baseline clinical predictors of transition. Linear mixed effects modelling was used to examine symptom severity. 28 % of CHARMS+ individuals transitioned to a Stage 2 disorder by 12-month follow-up. The CHARMS+ group had more severe symptoms at follow-up than the CHARMS- group. 96 % of Stage 2 transitions were initially to severe depression. Meeting criteria for multiple CHARMS subgroups was associated with higher transition risk: meeting one at-risk group = 24 %; meeting two at-risk groups = 17 %, meeting three at-risk groups = 55 %, meeting four at-risk groups = 50 %. The strongest baseline predictor of transition was severity of depressive symptoms. The CHARMS criteria identified a group of individuals at-risk of imminent onset of severe mental disorder, particularly severe depression. Larger scale studies and longer follow-up periods are required to validate and extend these findings.

An open label pilot trial of low-dose lithium for young people at ultra-high risk for psychosis.

AIM: Lithium, even at low doses, appears to offer neuroprotection against a wide variety of insults. In this controlled pilot, we examined the safety (i.e., side-effect profile) of lithium in a sample of young people identified at ultra-high risk (UHR) for psychosis. The secondary aim was to explore whether lithium provided a signal of clinical efficacy in reducing transition to psychosis compared with treatment as usual (TAU). METHODS: Young people attending the PACE clinic at Orygen, Melbourne, were prescribed a fixed dose (450 mg) of lithium (n = 25) or received TAU (n = 78). The primary outcome examined side-effects, with transition to psychosis, functioning and measures of psychopathology assessed as secondary outcomes. RESULTS: Participants in both groups were functionally compromised (lithium group GAF = 56.6; monitoring group GAF = 56.9). Side-effect assessment indicated that lithium was well-tolerated. 64% (n = 16) of participants in the lithium group were lithium-adherent to week 12. Few cases transitioned to psychosis across the study period; lithium group 4% (n = 1); monitoring group 7.7% (n = 6). There was no difference in time to transition to psychosis between the groups. No group differences were observed in other functioning and symptom domains, although all outcomes improved over time. CONCLUSIONS: With a side-effect profile either comparable to, or better than UHR antipsychotic trials, lithium might be explored for further research with UHR young people. A definitive larger trial is needed to determine the efficacy of lithium in this cohort.

Psychopathology and psychosocial functioning among young people with first-episode psychosis and/or first-presentation borderline personality disorder.

BACKGROUND: One in five young people with first-episode psychosis (FEP) also presents with borderline personality disorder (BPD) features. Among people diagnosed with BPD, auditory verbal hallucinations occur in 29-50 % and delusions in 10-100 %. Co-occurrence of psychotic symptoms and BPD is associated with greater clinical severity and greater difficulty accessing evidence based FEP care. This study aimed to investigate psychotic symptoms and psychosocial functioning among young people presenting to an early intervention mental health service. METHOD: According to the presence or absence of either FEP or BPD, 141 participants, aged 15-25 years, were assigned to one of four groups: FEP, BPD, combined FEP + BPD, or clinical comparison (CC) participants with neither FEP nor BPD. Participants completed semi-structured diagnostic interviews and interviewer and self-report measures of psychopathology and psychosocial functioning. RESULTS: The FEP + BPD group had significantly more severe psychopathology and poorer psychosocial functioning than the FEP group on every measure, apart from intensity of hallucinations. Comparing the FEP or BPD groups, the BPD group had greater psychopathology, apart from intensity of psychotic symptoms, which was significantly greater in the FEP group. These two groups did not significantly differ in their overall psychosocial functioning. Compared with CC young people, both the FEP + BPD and BPD groups differed significantly on every measure, with medium to large effect sizes. CONCLUSIONS: Young people with co-occurring FEP and BPD experience more severe difficulties than young people with either diagnosis alone. This combination of psychosis and severe personality pathology has been longitudinally associated with poorer outcomes among adults and requires specific clinical attention.

Combining Clinical With Cognitive or Magnetic Resonance Imaging Data for Predicting Transition to Psychosis in Ultra High-Risk Patients: Data From the PACE 400 Cohort.

BACKGROUND: Multimodal modeling that combines biological and clinical data shows promise in predicting transition to psychosis in individuals who are at ultra-high risk. Individuals who transition to psychosis are known to have deficits at baseline in cognitive function and reductions in gray matter volume in multiple brain regions identified by magnetic resonance imaging. METHODS: In this study, we used Cox proportional hazards regression models to assess the additive predictive value of each modality-cognition, cortical structure information, and the neuroanatomical measure of brain age gap-to a previously developed clinical model using functioning and duration of symptoms prior to service entry as predictors in the Personal Assessment and Crisis Evaluation (PACE) 400 cohort. The PACE 400 study is a well-characterized cohort of Australian youths who were identified as ultra-high risk of transitioning to psychosis using the Comprehensive Assessment of At Risk Mental States (CAARMS) and followed for up to 18 years; it contains clinical data (from N = 416 participants), cognitive data (n = 213), and magnetic resonance imaging cortical parameters extracted using FreeSurfer (n = 231). RESULTS: The results showed that neuroimaging, brain age gap, and cognition added marginal predictive information to the previously developed clinical model (fraction of new information: neuroimaging 0%-12%, brain age gap 7%, cognition 0%-16%). CONCLUSIONS: In summary, adding a second modality to a clinical risk model predicting the onset of a psychotic disorder in the PACE 400 cohort showed little improvement in the fit of the model for long-term prediction of transition to psychosis.

The self, neuroscience and psychosis study: Testing a neurophenomenological model of the onset of psychosis.

AIM: Basic self disturbance is a putative core vulnerability marker of schizophrenia spectrum disorders. The primary aims of the Self, Neuroscience and Psychosis (SNAP) study are to: (1) empirically test a previously described neurophenomenological self-disturbance model of psychosis by examining the relationship between specific clinical, neurocognitive, and neurophysiological variables in UHR patients, and (2) develop a prediction model using these neurophenomenological disturbances for persistence or deterioration of UHR symptoms at 12-month follow-up. METHODS: SNAP is a longitudinal observational study. Participants include 400 UHR individuals, 100 clinical controls with no attenuated psychotic symptoms, and 50 healthy controls. All participants complete baseline clinical and neurocognitive assessments and electroencephalography. The UHR sample are followed up for a total of 24 months, with clinical assessment completed every 6 months. RESULTS: This paper presents the protocol of the SNAP study, including background rationale, aims and hypotheses, design, and assessment procedures. CONCLUSIONS: The SNAP study will test whether neurophenomenological disturbances associated with basic self-disturbance predict persistence or intensification of UHR symptomatology over a 2-year follow up period, and how specific these disturbances are to a clinical population with attenuated psychotic symptoms. This may ultimately inform clinical care and pathoaetiological models of psychosis.

Brainwide Anatomical Connectivity and Prediction of Longitudinal Outcomes in Antipsychotic-Naïve First-Episode Psychosis.

BACKGROUND: Disruptions of axonal connectivity are thought to be a core pathophysiological feature of psychotic illness, but whether they are present early in the illness, prior to antipsychotic exposure, and whether they can predict clinical outcome remain unknown. METHODS: We acquired diffusion-weighted magnetic resonance images to map structural connectivity between each pair of 319 parcellated brain regions in 61 antipsychotic-naïve individuals with first-episode psychosis (15-25 years, 46% female) and a demographically matched sample of 27 control participants. Clinical follow-up data were also acquired in patients 3 and 12 months after the scan. We used connectome-wide analyses to map disruptions of inter-regional pairwise connectivity and connectome-based predictive modeling to predict longitudinal change in symptoms and functioning. RESULTS: Individuals with first-episode psychosis showed disrupted connectivity in a brainwide network linking all brain regions compared with controls (familywise error-corrected p = .03). Baseline structural connectivity significantly predicted change in functioning over 12 months (r = 0.44, familywise error-corrected p = .041), such that lower connectivity within fronto-striato-thalamic systems predicted worse functional outcomes. CONCLUSIONS: Brainwide reductions of structural connectivity exist during the early stages of psychotic illness and cannot be attributed to antipsychotic medication. Moreover, baseline measures of structural connectivity can predict change in patient functional outcomes up to 1 year after engagement with treatment services.

The Addition of Fish Oil to Cognitive Behavioral Case Management for Youth Depression: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Clinical Trial.

BACKGROUND: Clinical trials suggest that long-chain omega-3 polyunsaturated fatty acids (n-3 PUFAs) (fish oil) may reduce depressive symptoms in adults with major depressive disorder. Therefore, n-3 PUFAs may be a potential treatment for depression in youth. METHODS: Participants were 15- to-25 year-old individuals with major depressive disorder who sought care in one of three government-funded mental health services for young people in metropolitan Melbourne, Perth, or Sydney, Australia. Participants were randomly assigned in a double-blind, parallel-arm design to receive either fish oil (840 mg of eicosapentaenoic acid and 560 mg of docosahexaenoic acid) or placebo capsules as adjunct to cognitive behavioral case management. All participants were offered 50-minute cognitive behavioral case management sessions every 2 weeks delivered by qualified therapists (treatment as usual) at the study sites during the intervention period. The primary outcome was change in the interviewer-rated Quick Inventory of Depressive Symptomatology, Adolescent Version, score at 12 weeks. Erythrocyte n-3 PUFA levels were assessed pre-post intervention. RESULTS: A total of 233 young people were randomized to the treatment arms: 115 participants to the n-3 PUFA group and 118 to the placebo group. Mean change from baseline in the Quick Inventory of Depressive Symptomatology score was -5.8 in the n-3 PUFA group and -5.6 in the placebo group (mean difference, 0.2; 95% CI, -1.1 to 1.5; p = .75). Erythrocyte PUFA levels were not associated with depression severity at any time point. The incidence and severity of adverse events were similar in the two groups. CONCLUSIONS: This placebo-controlled trial and biomarker analysis found no evidence to support the use of fish oil for treatment in young people with major depressive disorder.

Psychosis Risk: Time to Look Empirically at a First-step Economical-pragmatic Way to Examine Anomalous Self-experience. Exploring the SQuEASE-11.

BACKGROUND: Since the late 1990s, there has been a worldwide surge of scientific interest in the pre-psychotic phase, resulting in the introduction of several clinical tools for early detection. The predictive accuracy of these tools has been limited, motivating the need for methodological and perspectival improvements. The EASE manual supports systematic assessment of anomalous self-experience, and proposes an overall model of understanding how most psychotic experiences may be initially generated on the basis of a unifying, fundamental, pre-reflective distortion of subjectivity. STUDY DESIGN: The EASE is time-consuming, so in order to spread the use of this essential perspective of psychosis risk we selected prototypical and frequent phenomena from the EASE, combining them into SQuEASE-11. To investigate this instrument for clinical relevance, basic psychometric properties, factor structure, and relationships with gold standard instruments and the full EASE, it was administered as an interview in the STEP intervention trial (Melbourne, Australia), with 328 clinical high-risk for psychosis (CHR-P) patients. STUDY RESULTS: The SQuEASE-11 had moderate internal consistency and revealed two correlated factors. Significant relationships were observed between the SQuEASE-11 and the widely used and validated instruments CAARMS, BPRS, SANS, MADRS, DACOBS, and SOFAS. The correlation with the full EASE was very strong. CONCLUSIONS: These 11 items do not necessarily relate specifically to ipseity disturbance, but the SQuEASE-11 seems to be a clinically relevant and brief supplementary first-line interview in CHR-P subjects. It may give a qualified indication of the need for a complete EASE interview, and it may also, importantly, inform treatment planning.

Development and temporal validation of a clinical prediction model of transition to psychosis in individuals at ultra-high risk in the UHR 1000+ cohort.

The concept of ultra-high risk for psychosis (UHR) has been at the forefront of psychiatric research for several decades, with the ultimate goal of preventing the onset of psychotic disorder in high-risk individuals. Orygen (Melbourne, Australia) has led a range of observational and intervention studies in this clinical population. These datasets have now been integrated into the UHR 1000+ cohort, consisting of a sample of 1,245 UHR individuals with a follow-up period ranging from 1 to 16.7 years. This paper describes the cohort, presents a clinical prediction model of transition to psychosis in this cohort, and examines how predictive performance is affected by changes in UHR samples over time. We analyzed transition to psychosis using a Cox proportional hazards model. Clinical predictors for transition to psychosis were investigated in the entire cohort using multiple imputation and Rubin's rule. To assess performance drift over time, data from 1995-2016 were used for initial model fitting, and models were subsequently validated on data from 2017-2020. Over the follow-up period, 220 cases (17.7%) developed a psychotic disorder. Pooled hazard ratio (HR) estimates showed that the Comprehensive Assessment of At-Risk Mental States (CAARMS) Disorganized Speech subscale severity score (HR=1.12, 95% CI: 1.02-1.24, p=0.024), the CAARMS Unusual Thought Content subscale severity score (HR=1.13, 95% CI: 1.03-1.24, p=0.009), the Scale for the Assessment of Negative Symptoms (SANS) total score (HR=1.02, 95% CI: 1.00-1.03, p=0.022), the Social and Occupational Functioning Assessment Scale (SOFAS) score (HR=0.98, 95% CI: 0.97-1.00, p=0.036), and time between onset of symptoms and entry to UHR service (log transformed) (HR=1.10, 95% CI: 1.02-1.19, p=0.013) were predictive of transition to psychosis. UHR individuals who met the brief limited intermittent psychotic symptoms (BLIPS) criteria had a higher probability of transitioning to psychosis than those who met the attenuated psychotic symptoms (APS) criteria (HR=0.48, 95% CI: 0.32-0.73, p=0.001) and those who met the Trait risk criteria (a first-degree relative with a psychotic disorder or a schizotypal personality disorder plus a significant decrease in functioning during the previous year) (HR=0.43, 95% CI: 0.22-0.83, p=0.013). Models based on data from 1995-2016 displayed good calibration at initial model fitting, but showed a drift of 20.2-35.4% in calibration when validated on data from 2017-2020. Large-scale longitudinal data such as those from the UHR 1000+ cohort are required to develop accurate psychosis prediction models. It is critical to assess existing and future risk calculators for temporal drift, that may reduce their utility in clinical practice over time.

Relationship between vocational status and perceived stress and daily hassles in first-episode psychosis: an exploratory study.

PURPOSE: Vocational recovery is a primary treatment goal of young people with first-episode psychosis (FEP), yet treatment in this domain is often delayed due to concerns that it might be too stressful. This study aimed to examine whether a relationship exists between vocational status and level of perceived stress and daily hassles in FEP. METHODS: Forty-seven FEP participants were recruited upon admission to the Early Psychosis Prevention and Intervention Centre (EPPIC), Melbourne. Demographics, psychopathology, perceived stress (Perceived Stress Scale; PSS) and daily hassles (Hassles Scale; HS) were measured. RESULTS: Regarding vocational status, 19 participants were unemployed, 13 were employed, 14 were students, and 1 reported 'home duties'. ANOVAs and post hoc tests comparing the first three groups on perceived stress and daily hassles revealed that the mean PSS Total and mean PSS Distress scores of the employed group were significantly lower than those of the unemployed and student groups. Regarding hassles scores, the employed group had a significantly lower mean Hassles Intensity score than the unemployed group. Results were largely unchanged when covariates were included. There were no significant differences between the three groups in levels of anxiety, negative or positive symptoms. The employed group reported lower depression than the student group, but this finding disappeared after controlling for gender. CONCLUSIONS: These results provide preliminary evidence supporting the notion that working or studying is not associated with increased perceived stress or daily hassles in FEP. The findings require replication in larger samples and in different phases of psychosis.

The association between stressful experiences and OCD symptoms in young adults at transdiagnostic risk.

BACKGROUND: It is unclear whether there is a specific association between stressful experiences and obsessive-compulsive symptoms or whether this relationship is due to stressful experiences increasing risk for psychopathology generally. AIMS: The current study examined the association between stressful experiences and obsessive-compulsive symptom dimensions, while adjusting for coexisting psychiatric symptoms and psychological distress in a young adult transdiagnostic at-risk sample. METHODS: Forty-three participants completed self-report measures assessing obsessive-compulsive symptoms, stressful experiences, and a range of other psychiatric symptoms. Regression models examined the relationship between stressful experiences and different obsessive-compulsive symptoms dimensions (i.e., symmetry, fear of harm, contamination, and unacceptable thoughts), adjusting for the influence of coexisting psychiatric symptoms and psychological distress. RESULTS: The results showed that there was an association between stressful experiences and obsessive-compulsive symptoms dimension of symmetry. Symptoms of borderline personality disorder were positively associated with the obsessive-compulsive symptom dimensions of symmetry and fear of harm symptoms. Symptoms of psychosis were found to be negatively associated with the obsessive-compulsive symptoms dimension of fear of harm. CONCLUSIONS: These findings have implications for understanding the psychological mechanisms that underlie symmetry symptoms and highlight the need to study OCS dimensions separately to inform more precise, mechanism-targeted interventions.

Isolating the impact of antipsychotic medication on metabolic health: Secondary analysis of a randomized controlled trial of antipsychotic medication versus placebo in antipsychotic medication naïve first-episode psychosis (the STAGES study).

BACKGROUND: Cardiovascular and metabolic diseases are the leading contributors to the early mortality associated with psychotic disorders. To date, it has not been possible to disentangle the effect of medication and non-medication factors on the physical health of people with a first episode of psychosis (FEP). This study aimed to isolate the effects of antipsychotic medication on anthropometric measurements, fasting glucose and lipids. METHODS: This study utilized data from a triple-blind randomized placebo-controlled trial comparing two groups of antipsychotic-naïve young people with a FEP who were randomized to receive a second-generation antipsychotic medication (FEP-medication group) or placebo (FEP-placebo group) for 6 months. Twenty-seven control participants were also recruited. RESULTS: Eighty-one participants commenced the trial; 69.1% completed at least 3 months of the intervention and 33.3% completed the full 6 months. The FEP-placebo group gained a mean of 2.4 kg (±4.9) compared to 1.1 kg (±4.9) in the control participants (t = 0.76, p = .45). After controlling for multiple analyses, there was no difference in blood pressure, waist circumference or heart rate between the FEP-placebo group and controls. After 6 months, the FEP medication group had gained 4.1 kg (±4.5), higher than those receiving placebo but not statistically significant (t = 0.8, p = .44). There were no differences in fasting glucose or lipids between the FEP groups after 3 months. CONCLUSIONS: While limited by small numbers and high attrition, these findings indicate that some of the metabolic complications observed in psychotic disorders could be attributable to factors other than medication. This emphasizes the need to deliver physical health interventions early in the course of FEP.

Effects of risperidone/paliperidone versus placebo on cognitive functioning over the first 6 months of treatment for psychotic disorder: secondary analysis of a triple-blind randomised clinical trial.

The drivers of cognitive change following first-episode psychosis remain poorly understood. Evidence regarding the role of antipsychotic medication is primarily based on naturalistic studies or clinical trials without a placebo arm, making it difficult to disentangle illness from medication effects. A secondary analysis of a randomised, triple-blind, placebo-controlled trial, where antipsychotic-naive patients with first-episode psychotic disorder were allocated to receive risperidone/paliperidone or matched placebo plus intensive psychosocial therapy for 6 months was conducted. A healthy control group was also recruited. A cognitive battery was administered at baseline and 6 months. Intention-to-treat analysis involved 76 patients (antipsychotic medication group: 37; 18.6Mage [2.9] years; 21 women; placebo group: 39; 18.3Mage [2.7]; 22 women); and 42 healthy controls (19.2Mage [3.0] years; 28 women). Cognitive performance predominantly remained stable (working memory, verbal fluency) or improved (attention, processing speed, cognitive control), with no group-by-time interaction evident. However, a significant group-by-time interaction was observed for immediate recall (p = 0.023), verbal learning (p = 0.024) and delayed recall (p = 0.005). The medication group declined whereas the placebo group improved on each measure (immediate recall: p = 0.024; ηp2 = 0.062; verbal learning: p = 0.015; ηp2 = 0.072 both medium effects; delayed recall: p = 0.001; ηp2 = 0.123 large effect). The rate of change for the placebo and healthy control groups was similar. Per protocol analysis (placebo n = 16, medication n = 11) produced similar findings. Risperidone/paliperidone may worsen verbal learning and memory in the early months of psychosis treatment. Replication of this finding and examination of various antipsychotic agents are needed in confirmatory trials. Antipsychotic effects should be considered in longitudinal studies of cognition in psychosis.Trial registration: Australian New Zealand Clinical Trials Registry ( http://www.anzctr.org.au/ ; ACTRN12607000608460).

Gradients of striatal function in antipsychotic-free first-episode psychosis and schizotypy.

Both psychotic illness and subclinical psychosis-like experiences (PLEs) have been associated with cortico-striatal dysfunction. This work has largely relied on a discrete parcellation of the striatum into distinct functional areas, but recent evidence suggests that the striatum comprises multiple overlapping and smoothly varying gradients (i.e., modes) of functional organization. Here, we investigated two of these functional connectivity modes, previously associated with variations in the topographic patterning of cortico-striatal connectivity (first-order gradient), and dopaminergic innervation of the striatum (second-order gradient), and assessed continuities in striatal function from subclinical to clinical domains. We applied connectopic mapping to resting-state fMRI data to obtain the first-order and second-order striatal connectivity modes in two distinct samples: (1) 56 antipsychotic-free patients (26 females) with first-episode psychosis (FEP) and 27 healthy controls (17 females); and (2) a community-based cohort of 377 healthy individuals (213 females) comprehensively assessed for subclinical PLEs and schizotypy. The first-order "cortico-striatal" and second-order "dopaminergic" connectivity gradients were significantly different in FEP patients compared to controls bilaterally. In the independent sample of healthy individuals, variations in the left first-order "cortico-striatal" connectivity gradient were associated with inter-individual differences in a factor capturing general schizotypy and PLE severity. The presumed cortico-striatal connectivity gradient was implicated in both subclinical and clinical cohorts, suggesting that variations in its organization may represent a neurobiological trait marker across the psychosis continuum. Disruption of the presumed dopaminergic gradient was only noticeable in patients, suggesting that neurotransmitter dysfunction may be more apparent to clinical illness.

Network-Based Spreading of Gray Matter Changes Across Different Stages of Psychosis.

Importance: Psychotic illness is associated with anatomically distributed gray matter reductions that can worsen with illness progression, but the mechanisms underlying the specific spatial patterning of these changes is unknown. Objective: To test the hypothesis that brain network architecture constrains cross-sectional and longitudinal gray matter alterations across different stages of psychotic illness and to identify whether certain brain regions act as putative epicenters from which volume loss spreads. Design, Settings, and Participants: This case-control study included 534 individuals from 4 cohorts, spanning early and late stages of psychotic illness. Early-stage cohorts included patients with antipsychotic-naive first-episode psychosis (n = 59) and a group of patients receiving medications within 3 years of psychosis onset (n = 121). Late-stage cohorts comprised 2 independent samples of people with established schizophrenia (n = 136). Each patient group had a corresponding matched control group (n = 218). A sample of healthy adults (n = 356) was used to derive representative structural and functional brain networks for modeling of network-based spreading processes. Longitudinal illness-related and antipsychotic-related gray matter changes over 3 and 12 months were examined using a triple-blind randomized placebo-control magnetic resonance imaging study of the antipsychotic-naive patients. All data were collected between April 29, 2008, and January 15, 2020, and analyses were performed between March 1, 2021, and January 14, 2023. Main Outcomes and Measures: Coordinated deformation models were used to estimate the extent of gray matter volume (GMV) change in each of 332 parcellated areas by the volume changes observed in areas to which they were structurally or functionally coupled. To identify putative epicenters of volume loss, a network diffusion model was used to simulate the spread of pathology from different seed regions. Correlations between estimated and empirical spatial patterns of GMV alterations were used to quantify model performance. Results: Of 534 included individuals, 354 (66.3%) were men, and the mean (SD) age was 28.4 (7.4) years. In both early and late stages of illness, spatial patterns of cross-sectional volume differences between patients and controls were more accurately estimated by coordinated deformation models constrained by structural, rather than functional, network architecture (r range, >0.46 to <0.57; P < .01). The same model also robustly estimated longitudinal volume changes related to illness (r ≥ 0.52; P < .001) and antipsychotic exposure (r ≥ 0.50; P < .004). Network diffusion modeling consistently identified, across all 4 data sets, the anterior hippocampus as a putative epicenter of pathological spread in psychosis. Epicenters of longitudinal GMV loss were apparent in posterior cortex early in the illness and shifted to the prefrontal cortex with illness progression. Conclusion and Relevance: These findings highlight a central role for white matter fibers as conduits for the spread of pathology across different stages of psychotic illness, mirroring findings reported in neurodegenerative conditions. The structural connectome thus represents a fundamental constraint on brain changes in psychosis, regardless of whether these changes are caused by illness or medication. Moreover, the anterior hippocampus represents a putative epicenter of early brain pathology from which dysfunction may spread to affect connected areas.

A Sequential Adaptive Intervention Strategy Targeting Remission and Functional Recovery in Young People at Ultrahigh Risk of Psychosis: The Staged Treatment in Early Psychosis (STEP) Sequential Multiple Assignment Randomized Trial.

Importance: Clinical trials have not established the optimal type, sequence, and duration of interventions for people at ultrahigh risk of psychosis. Objective: To determine the effectiveness of a sequential and adaptive intervention strategy for individuals at ultrahigh risk of psychosis. Design, Setting, and Participants: The Staged Treatment in Early Psychosis (STEP) sequential multiple assignment randomized trial took place within the clinical program at Orygen, Melbourne, Australia. Individuals aged 12 to 25 years who were seeking treatment and met criteria for ultrahigh risk of psychosis according to the Comprehensive Assessment of At-Risk Mental States were recruited between April 2016 and January 2019. Of 1343 individuals considered, 342 were recruited. Interventions: Step 1: 6 weeks of support and problem solving (SPS); step 2: 20 weeks of cognitive-behavioral case management (CBCM) vs SPS; and step 3: 26 weeks of CBCM with fluoxetine vs CBCM with placebo with an embedded fast-fail option of ω-3 fatty acids or low-dose antipsychotic medication. Individuals who did not remit progressed through these steps; those who remitted received SPS or monitoring for up to 12 months. Main Outcomes and Measures: Global Functioning: Social and Role scales (primary outcome), Brief Psychiatric Rating Scale, Scale for the Assessment of Negative Symptoms, Montgomery-Åsberg Depression Rating Scale, quality of life, transition to psychosis, and remission and relapse rates. Results: The sample comprised 342 participants (198 female; mean [SD] age, 17.7 [3.1] years). Remission rates, reflecting sustained symptomatic and functional improvement, were 8.5%, 10.3%, and 11.4% at steps 1, 2, and 3, respectively. A total of 27.2% met remission criteria at any step. Relapse rates among those who remitted did not significantly differ between SPS and monitoring (step 1: 65.1% vs 58.3%; step 2: 37.7% vs 47.5%). There was no significant difference in functioning, symptoms, and transition rates between SPS and CBCM and between CBCM with fluoxetine and CBCM with placebo. Twelve-month transition rates to psychosis were 13.5% (entire sample), 3.3% (those who ever remitted), and 17.4% (those with no remission). Conclusions and Relevance: In this sequential multiple assignment randomized trial, transition rates to psychosis were moderate, and remission rates were lower than expected, partly reflecting the ambitious criteria set and challenges with real-world treatment fidelity and adherence. While all groups showed mild to moderate functional and symptomatic improvement, this was typically short of remission. While further adaptive trials that address these challenges are needed, findings confirm substantial and sustained morbidity and reveal relatively poor responsiveness to existing treatments. Trial Registration: ClinicalTrials.gov Identifier: NCT02751632.

Pineal morphology of the clinical high-risk state for psychosis and different psychotic disorders.

BACKGROUND: Pineal volume reductions have been reported in schizophrenia and clinical high-risk states for the development of psychosis, supporting the role of melatonin dysregulation in the pathophysiology of psychosis. However, it remains unclear whether pineal volume is associated with the later onset of psychosis in individuals at clinical high-risk (CHR) of psychosis or if pineal atrophy is specific to schizophrenia among different psychotic disorders. METHODS: This magnetic resonance imaging study examined the volume of and cyst prevalence in the pineal gland in 135 individuals at CHR of psychosis [52 (38.5%) subsequently developed psychosis], 162 with first-episode psychosis (FEP), 89 with chronic schizophrenia, and 87 healthy controls. The potential contribution of the pineal morphology to clinical characteristics was also examined in the CHR and FEP groups. RESULTS: Pineal volumes did not differ significantly between the CHR, FEP, and chronic schizophrenia groups, but were significantly smaller than that in healthy controls. However, pineal volumes were not associated with the later onset of psychosis in the CHR group or FEP sub-diagnosis (i.e., schizophrenia, schizophreniform disorder, affective psychosis, and other psychoses). No significant differences were observed in the prevalence of pineal cysts between the groups, and it also did not correlate with clinical characteristics in the CHR and FEP groups. CONCLUSION: These results suggest that pineal atrophy is a general vulnerability marker of psychosis, while pineal cysts do not appear to contribute to the pathophysiology of psychosis.