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.

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.

Cognitive health treatment priorities and preferences among young people with mental illness: The your mind, your choice survey.

AIM: Cognitive impairments negatively impact the everyday functioning of young people with mental illness. However, no previous study has asked young people (1) how much of a priority cognitive functioning is within mental health treatment, and (2) what types of cognition-focused treatments are most appealing. The current study aimed to address these questions. METHODS: Your Mind, Your Choice was a survey-based study involving an Australian sample of young people who were receiving mental health treatment. The survey asked participants to (1) provide demographic and mental health history, (2) rate the importance of 20 recovery domains, including cognition, when receiving mental health treatment, (3) share their experiences of cognitive functioning, and (4) rate their likelihood of trying 14 different behavioural, biochemical, and physical treatments that may address cognitive functioning. RESULTS: Two-hundred and forty-three participants (Mage = 20.07, SD = 3.25, range = 15-25, 74% female) completed the survey. Participants reported that addressing cognitive functioning in mental health care was very important (M = 76.33, SD = 20.7, rated on a scale from 0 = not important to 100 = extremely important), ranking cognition among their top six treatment needs. Seventy percent of participants reported experiencing cognitive difficulties, but less than one-third had received treatment for these difficulties. Compensatory training, sleep interventions and psychoeducation were ranked as treatments that participants were most likely to try to support their cognitive functioning. CONCLUSIONS: Young people with mental ill-health commonly experience cognitive difficulties and would like this to be a focus of treatment; however, this need is often unmet and should be a focus of research and implementation.

The prevalence of vitamin D deficiency and associated factors in first-episode psychosis.

AIM: Vitamin D deficiency is prevalent in people with established psychotic disorders, but less is known about vitamin D levels in people with first-episode psychosis (FEP). This study aimed to determine the prevalence of vitamin D deficiency in people with FEP and identify the factors associated with vitamin D status. METHODS: This was a prospective cohort study nested within a randomized controlled trial, which included 37 young people with an FEP with minimal antipsychotic medication exposure. RESULTS: Twenty-four percent of participants were vitamin D deficient, and a further 30% were vitamin D insufficient. There was no association between vitamin D and demographic factors or clinical symptoms (positive, negative, general psychopathology and depressive symptoms) or cognition and functioning. However, vitamin D levels were associated with season of sampling. CONCLUSIONS: Considering the longer-term adverse effects associated with vitamin D deficiency, it is warranted to ensure this clinical population receives supplementation if indicated.

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.

Delivery of Neuropsychological Interventions for Adult and Older Adult Clinical Populations: An Australian Expert Working Group Clinical Guidance Paper.

Delivery of neuropsychological interventions addressing the cognitive, psychological, and behavioural consequences of brain conditions is increasingly recognised as an important, if not essential, skill set for clinical neuropsychologists. It has the potential to add substantial value and impact to our role across clinical settings. However, there are numerous approaches to neuropsychological intervention, requiring different sets of skills, and with varying levels of supporting evidence across different diagnostic groups. This clinical guidance paper provides an overview of considerations and recommendations to help guide selection, delivery, and implementation of neuropsychological interventions for adults and older adults. We aimed to provide a useful source of information and guidance for clinicians, health service managers, policy-makers, educators, and researchers regarding the value and impact of such interventions. Considerations and recommendations were developed by an expert working group of neuropsychologists in Australia, based on relevant evidence and consensus opinion in consultation with members of a national clinical neuropsychology body. While the considerations and recommendations sit within the Australian context, many have international relevance. We include (i) principles important for neuropsychological intervention delivery (e.g. being based on biopsychosocial case formulation and person-centred goals); (ii) a description of clinical competencies important for effective intervention delivery; (iii) a summary of relevant evidence in three key cohorts: acquired brain injury, psychiatric disorders, and older adults, focusing on interventions with sound evidence for improving activity and participation outcomes; (iv) an overview of considerations for sustainable implementation of neuropsychological interventions as 'core business'; and finally, (v) a call to action.

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.

Impact of rural settings on the interpersonal and personal processes associated with young people supporting a peer who experienced a traumatic event.

INTRODUCTION: There is limited research into informal support processes amongst young people supporting a peer through a traumatic event and how this process occurs specifically within a rural setting. OBJECTIVE: The aim of this research was to understand how the contextual environment impacts on the personal and interpersonal processes of rural-based young people supporting a peer who experienced a traumatic event. DESIGN: Qualitative interviews were conducted with 22 young people (aged 14-19), who resided in Gippsland, Victoria, Australia. A substantive theory was developed using Charmaz's (1) Constructivist grounded theory methodology. FINDINGS: Young people who shared responsibility for supporting their peer went back to life as normal and felt connected to their community, whereas young people who maintained sole responsibility, experienced mental health problems, disconnected from their community and felt like an outsider. The contextual environmental factors (i.e., service accessibility, limited transport, and internet blackspots) impacted both negatively and positively on young people's ability to provide support as well as influenced whether they felt safe share responsibility. DISCUSSION: This theory implies that providing pathways to reconnecting with place and community, are essential in guiding young people back to their foundations of support. CONCLUSION: Integrating these insights can create new service models in rural areas, whilst also creating opportunities to form healthy foundations of support.

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.

Prevalence of cognitive impairments and strengths in the early course of psychosis and depression.

BACKGROUND: Studies investigating cognitive impairments in psychosis and depression have typically compared the average performance of the clinical group against healthy controls (HC), and do not report on the actual prevalence of cognitive impairments or strengths within these clinical groups. This information is essential so that clinical services can provide adequate resources to supporting cognitive functioning. Thus, we investigated this prevalence in individuals in the early course of psychosis or depression. METHODS: A comprehensive cognitive test battery comprising 12 tests was completed by 1286 individuals aged 15-41 (mean age 25.07, s.d. 5.88) from the PRONIA study at baseline: HC (N = 454), clinical high risk for psychosis (CHR; N = 270), recent-onset depression (ROD; N = 267), and recent-onset psychosis (ROP; N = 295). Z-scores were calculated to estimate the prevalence of moderate or severe deficits or strengths (>2 s.d. or 1-2 s.d. below or above HC, respectively) for each cognitive test. RESULTS: Impairment in at least two cognitive tests was as follows: ROP (88.3% moderately, 45.1% severely impaired), CHR (71.2% moderately, 22.4% severely impaired), ROD (61.6% moderately, 16.2% severely impaired). Across clinical groups, impairments were most prevalent in tests of working memory, processing speed, and verbal learning. Above average performance (>1 s.d.) in at least two tests was present for 40.5% ROD, 36.1% CHR, 16.1% ROP, and was >2 SDs in 1.8% ROD, 1.4% CHR, and 0% ROP. CONCLUSIONS: These findings suggest that interventions should be tailored to the individual, with working memory, processing speed, and verbal learning likely to be important transdiagnostic targets.

Foundations of support: Processes associated with adolescents supporting a peer who experienced a traumatic event.

BACKGROUND: There is limited research on how supporting a peer through a traumatic event is experienced by adolescents. The aim of this research was to understand the personal and interpersonal processes of adolescents supporting a peer who experienced a traumatic event based on youth definitions. METHOD: In-depth qualitative interviews were conducted with 22 adolescents aged 14-19, residing in Gippsland, Victoria, Australia. A constructivist grounded theory methodology was used to develop a substantive theory. RESULTS: The substantive theory 'Foundations of Support' was developed which explained the support process phenomena. Specifically, adolescents who had shared responsibility for supporting their peers went back to life as normal, whereas adolescents who maintained sole responsibility experienced mental health problems. DISCUSSION: The 'Foundations of Support' grounded theory highlights the importance of adolescents having strong connections to their trusted others, such as family, friends and community. This theory implies that facilitating connections with positive supports such as place and community are essential in guiding adolescents back to their foundations of support. Without strong connections, adolescents are at risk of maintaining sole responsibility, losing their sense of identity and feeling alienated within their community.

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).

Acceptability and feasibility of a multidomain harmonized data collection protocol in youth mental health.

OBJECTIVE: To develop targeted treatment for young people experiencing mental illness, a better understanding of the biological, psychological, and social changes is required, particularly during the early stages of illness. To do this, large datasets need to be collected using standardized methods. A harmonized data collection protocol was tested in a youth mental health research setting to determine its acceptability and feasibility. METHOD: Eighteen participants completed the harmonization protocol, including a clinical interview, self-report measures, neurocognitive measures, and mock assessments of magnetic resonance imaging (MRI) and blood. The feasibility of the protocol was assessed by recording recruitment rates, study withdrawals, missing data, and protocol deviations. Subjective responses from participant surveys and focus groups were used to examine the acceptability of the protocol. RESULTS: Twenty-eight young people were approached, 18 consented, and four did not complete the study. Most participants reported positive subjective impressions of the protocol as a whole and showed interest in participating in the study again, if given the opportunity. Participants generally perceived the MRI and neurocognitive tasks as interesting and suggested that the assessment of clinical presentation could be shortened. CONCLUSION: Overall, the harmonized data collection protocol appeared to be feasible and generally well-accepted by participants. With a majority of participants finding the assessment of clinical presentation too long and repetitive, the authors have made suggestions to shorten the self-reports. The broader implementation of this protocol could allow researchers to create large datasets and better understand how psychopathological and neurobiological changes occur in young people with mental ill-health.

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.

The use of implementation science to close the research-to-treatment gap for cognitive impairment in psychosis.

For people living with psychosis, cognitive impairment is common and can have significant impacts for functional recovery, impacting engagement with treatment and quality of life more broadly. There is now strong evidence for the effectiveness of cognition-focused treatments, such as cognitive remediation to improve clinical and functional outcomes for people with psychosis. However, engagement with treatment has been a long-standing issue in mental health care, including for people with psychosis, who often experience difficulties with motivation. While research on clinical effectiveness of cognition-focused treatment is growing, to date there has been little research focused on the implementation of such treatments and it is not clear how best to support uptake and engagement across diverse mental health settings. Implementation science is the study of methods and strategies to promote the adoption, application, and maintenance of evidence-based practices in routine care. To integrate cognition-focused treatments into routine practice, and improve engagement with treatment and the quality and effectiveness of care for people with psychosis, researchers need to embrace implementation science and research. This paper provides a succinct overview of the field of implementation science, current evidence for implementation of cognition-focused treatments for psychosis and practical guidance for using implementation science in clinical research. The future of psychosis research includes multidisciplinary teams of clinical researchers and implementation scientists, working together with providers and consumers to build the evidence that can improve the implementation of cognition-focused treatments.

Frontostriatothalamic effective connectivity and dopaminergic function in the psychosis continuum.

Dysfunction of fronto-striato-thalamic (FST) circuits is thought to contribute to dopaminergic dysfunction and symptom onset in psychosis, but it remains unclear whether this dysfunction is driven by aberrant bottom-up subcortical signalling or impaired top-down cortical regulation. We used spectral dynamic causal modelling of resting-state functional MRI to characterize the effective connectivity of dorsal and ventral FST circuits in a sample of 46 antipsychotic-naïve first-episode psychosis patients and 23 controls and an independent sample of 36 patients with established schizophrenia and 100 controls. We also investigated the association between FST effective connectivity and striatal 18F-DOPA uptake in an independent healthy cohort of 33 individuals who underwent concurrent functional MRI and PET. Using a posterior probability threshold of 0.95, we found that midbrain and thalamic connectivity were implicated as dysfunctional across both patient groups. Dysconnectivity in first-episode psychosis patients was mainly restricted to the subcortex, with positive symptom severity being associated with midbrain connectivity. Dysconnectivity between the cortex and subcortical systems was only apparent in established schizophrenia patients. In the healthy 18F-DOPA cohort, we found that striatal dopamine synthesis capacity was associated with the effective connectivity of nigrostriatal and striatothalamic pathways, implicating similar circuits to those associated with psychotic symptom severity in patients. Overall, our findings indicate that subcortical dysconnectivity is evident in the early stages of psychosis, that cortical dysfunction may emerge later in the illness, and that nigrostriatal and striatothalamic signalling are closely related to striatal dopamine synthesis capacity, which is a robust marker for psychosis.