Subthreshold Psychotic Symptoms Research Articles

Exploring the associations between momentary cortisol levels and psychotic-like experiences in young adults: Results from a temporal network analysis of daily-life data.

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the development of psychosis and subthreshold psychotic symptoms commonly referred to as psychotic-like experiences (PLEs). The exact mechanisms linking the HPA axis responses with the emergence of PLEs remain unknown. The present study aimed to explore real-life associations between stress, negative affect, salivary cortisol levels (a proxy of the HPA axis activity) as well as PLEs together with their underlying cognitive biases (i.e., threat anticipation and aberrant salience). The study was based on the experience sampling method scheduled over 7 consecutive days in the sample of 77 drug-naïve, young adults (18-35 years). The saliva samples were collected with each prompt to measure cortisol levels. A temporal network analysis was used to explore the directed associations of tested variables. Altogether, 3234 data entries were analyzed. Data analysis revealed that salivary cortisol levels did not directly predict next-moment fluctuations of PLEs. However, higher salivary cortisol levels were associated with higher next-moment levels of PLEs through the effects on threat anticipation and negative affect. In turn, PLEs appeared to predict cortisol levels through the effects on negative affect and event-related stress. Negative affect and threat anticipation were the most central nodes in the network. There might be bidirectional associations between the HPA axis responses and PLEs. Threat anticipation and negative affect might be the most important mediators of these associations. Interventions targeting these mediators might hold promise for disrupting the connection between the HPA axis dysregulation and PLEs.

Efficacy of the unified protocol for transdiagnostic treatment of comorbid emotional disorders in patients with ultra high risk for psychosis: Results of a randomized controlled trial

BackgroundThe most common reason for help-seeking in ultra-high risk (UHR) for psychosis patients is comorbid symptoms, mainly anxiety and depression. However, psychological interventions are mainly focused on subthreshold psychotic symptoms. There is a growing push to include transdiagnostic therapies in specialized intervention teams for psychosis in young people. The Unified Protocol for the Transdiagnostic Treatment of Emotional Disorders (UP) has demonstrated efficacy in emotional disorders, and its application has recently expanded to other pathologies such as borderline personality disorder (BPD) and bipolar disorder (BD). MethodsThis pilot study was conducted with 36 patients with UHR for psychosis and symptoms of comorbid emotional disorders who were receiving treatment in an early intervention programme for psychosis. This is a randomised control trial (RCT) with two conditions: treatment as usual (TAU) with the group and online application of the UP (UP+TAU) (n = 18) and TAU (n = 18). Evaluations were conducted at baseline, after treatment, and at the three-month follow-up. ResultsComorbid anxiety and depression symptoms improved significantly in patients in the UP+TAU group compared to those in the TAU. Significant improvements in negative affect, emotional dysregulation, neuroticism, extraversion, functioning, and quality of life were also observed, and satisfaction with the intervention was high. ConclusionsUP may be an acceptable and effective intervention for the treatment of symptoms of comorbid emotional disorders in patients with UHR for psychosis. LimitationsThe sample size was small, and further studies are needed to test this intervention with larger samples of patients with UHR for psychosis with emotional comorbidities.

Assessment of Psychotic Risk in a Sample of Children and Adolescents with Autism Spectrum Disorder Compared to a Group of "Clinical High Risk" Patients: A Preliminary Study.

Autism spectrum disorder and psychotic risk show several overlapping symptoms, so differential diagnosis is often difficult. In addition, there is a high rate of comorbidity between the two conditions, which further complicates the work of clinicians. We evaluated the presence of subthreshold psychotic symptoms and/or defined psychotic risk syndromes in autistic children and adolescents; we compared the prevalence, type, and severity of psychotic risk symptoms with those of a group of non-autistic patients at clinical high risk for psychosis (CHR-P). 2. In total, 23 autistic patients and 14 CHR-P patients without autism (aged 8-17) were enrolled in the study. The main assessment was made through clinical interviews for autism (Autism Diagnostic Observation Schedule, Second Edition-ADOS-2, Autism Diagnostic Interview, Revised-ADI-R) and psychotic risk (Schizophrenia Proneness Instrument, Child and Youth version-SPI-CY, Structured Interview for Psychosis Risk Syndromes-SIPS). 3. No above-threshold psychotic risk symptoms were detected in our autistic patients, but subthreshold psychotic symptoms were identified in all areas. Specific items from all four dimensions of SIPS appear to be more specific for psychotic risk than autism without comorbidity. 4. An a priori screening of psychotic risk in neurodiverse populations is fundamental to prevent more severe conditions. Research should clarify the effective specificity of the available tools to modify them to improve their detection capability.

Negative self-reference as a component of subthreshold psychotic symptoms in clinical high-risk youth.

Schizophrenia is a leading cause of disability worldwide; early detection and intervention are critical. Early in their illness, individuals at clinical high-risk (CHR) for psychosis have subthreshold psychotic symptoms that are often derogatory and self-directed. We hypothesized that CHR participants with negative self-reference (NSR) as a component of subthreshold psychosis would also have higher levels of social anxiety and depression, lower self-esteem and lower social/role/global functioning as compared with CHR participants without NSR. One hundred and sixty-eight participants from the National Institute of Mental Health (NIMH) funded Regroup Cognitive Behavioural Social Skills Training (CBSST) study were included. Clinical vignettes that included the Scale of Psychosis-Risk Symptoms were coded categorically to indicate whether NSR was present. t-tests were used to determine the association between NSR, symptom, and functional measures. Participants with NSR demonstrated significantly more social interaction anxiety (p < .001), negative beliefs about the self (p ≤ .001), defeatist beliefs (p < .05), depressive symptoms (p < .05) and positive symptoms (p < .005). There were no significant differences in social self-efficacy, positive or negative beliefs about others, positive beliefs about the self or psychosocial functioning between the two groups. Clinically significant differences were found between CHR participants with and without NSR, suggesting that this may be a useful factor to identify and address. Follow-up studies are needed to determine whether NSR responds to CBSST and whether or not its resolution would be associated with improvement in other symptom domains.

Assessing evidence supporting cannabis harm reduction practices for adolescents at clinical high-risk for psychosis: a review and clinical implementation tool.

Cannabis use is consistently associated with both increased incidence of frank psychotic disorders and acute exacerbations of psychotic symptoms in healthy individuals and people with psychosis spectrum disorders. Although there is uncertainty around causality, cannabis use may be one of a few modifiable risk factors for conversion to psychotic disorders in individuals with Clinical High Risk for Psychosis (CHR-P) syndromes, characterized by functionally impairing and distressing subthreshold psychotic symptoms. To date, few recommendations beyond abstinence to reduce adverse psychiatric events associated with cannabis use have been made. This narrative review synthesizes existing scientific literature on cannabis' acute psychotomimetic effects and epidemiological associations with psychotic disorders in both CHR-P and healthy individuals to bridge the gap between scientific knowledge and practical mental health intervention. There is compelling evidence for cannabis acutely exacerbating psychotic symptoms in CHR-P, but its impact on conversion to psychotic disorder is unclear. Current evidence supports a harm reduction approach in reducing frequency of acute psychotic-like experiences, though whether such interventions decrease CHR-P individuals' risk of conversion to psychotic disorder remains unknown. Specific recommendations include reducing frequency of use, lowering delta-9-tetrahydrocannabinol content in favor of cannabidiol-only products, avoiding products with inconsistent potency like edibles, enhancing patient-provider communication about cannabis use and psychotic-like experiences, and utilizing a collaborative and individualized therapeutic approach. Despite uncertainty surrounding cannabis' causal association with psychotic disorders, cautious attempts to reduce acute psychosis risk may benefit CHR-P individuals uninterested in abstinence. Further research is needed to clarify practices associated with minimization of cannabis-related psychosis risk.

Brief rapport: Perceptual aberration in patients at ultra-high risk for psychosis.

Ultra-high risk (UHR) is considered a forerunner of psychosis, but most UHR individuals do not later convert, yet remain symptomatic, disabled and help-seeking. Thus, there is an increased recognition of the UHR phenotype as a syndrome in itself, rather than merely a risk syndrome. It is therefore essential to investigate outcomes other than transition to psychosis. For this purpose, perceptual aberration appears to be a distinct, as well as a stable and less state-specific vulnerability indicator. We aimed to investigate perceptual aberration and associations with functional, neuro and social cognitive risk factors in an UHR sample. One hundred and twenty UHR and 64 healthy controls were compared on levels of perceptual aberration using the perceptual aberration scale. We further investigated cross-sectional associations between perceptual aberration and CAARMS (as a measure of subthreshold psychotic symptoms) and functional, neuro and social cognitive risk factors within the UHR using Spearmans ρ. Perceptual aberration was significantly higher in UHR than in healthy controls and was associated with social functioning, executive functioning, and emotion recognition. Our findings are consistent with a view of perceptual aberration as a stable vulnerability indicator that varies little with clinical state.

Applying the Unified Protocol for Transdiagnostic Treatment of Emotional Disorders in a Case of Ultra-High Risk for Psychosis With Emotional Comorbidity

This case study aims to describe the application of the Unified Protocol (UP) for Transdiagnostic Treatment of Emotional Disorders in the case of a 30-year-old patient with a diagnosis of Ultra-high Risk for Psychosis (UHR) and comorbid anxiety and depression. UP is a psychological intervention that uses cognitive-behavioral techniques whose objective is to reduce emotional dysregulation, which is one of the transdiagnostic mechanisms of emotional disorders. UP has demonstrated its efficacy in samples of patients with emotional disorders. Frank was a 30-year-old man diagnosed with UHR and other emotional disorders (major depressive disorder, bulimia nervosa, generalized anxiety disorder, and social anxiety disorder) who underwent the UP intervention in 15 group and online sessions, lasting 2 hours each, over the course of 4 months. At the 6-month follow-up evaluation, Frank presented significant improvement in all emotional and functioning variables: anxious and depressive symptoms, negative and positive affect, neuroticism and extraversion, emotional dysregulation, maladjustment, and quality of life. There was also a reduction in subthreshold psychotic symptoms. Frank no longer met the criteria for any emotional disorder. We also found an improvement trend, although not significant, in other variables such as insight and cognitive biases measured with specific questionnaires for psychosis. Frank attended all treatment and follow-up sessions and rated the program very positively. UP may be a clinically useful treatment for young people with comorbid UHR and emotional disorders in the early stages of mental health illnesses that could improve clinical and functional outcomes.

Transsyndromic trajectories from pre-onset self-harm and subthreshold psychosis to the first episode of psychosis: A longitudinal study.

Across subthreshold psychotic and nonpsychotic syndromes, symptoms experienced before the onset of a first episode of psychosis (FEP) may index distinct illness trajectories. We aimed to examine the associations between three types of pre-onset symptoms (self-harm, suicide attempts, and subthreshold psychotic) and outcome trajectories during FEP. Participants with FEP were recruited from PEPP-Montreal, a catchment-based early intervention service. Pre-onset symptoms were systematically assessed through interviews with participants (and their relatives) and reviews of health and social records. Over 2 years of follow-up at PEPP-Montreal, 3-8 repeated measures were collected for positive, negative, depressive, and anxiety symptoms, as well as functioning. We applied linear mixed models to examine associations between pre-onset symptoms and outcome trajectories. We found that on average over follow-up, participants with pre-onset self-harm had more severe positive, depressive, and anxiety symptoms compared with other participants (standardized mean differences: 0.32-0.76), while differences in negative symptoms and functioning were not significant. Associations did not differ by gender and remained similar after adjusting for the duration of untreated psychosis, substance use disorder, or baseline diagnosis of affective psychosis. Over time, depressive and anxiety symptoms improved among individuals with pre-onset self-harm, such that they converged with other individuals by the end of the follow-up. Similarly, pre-onset suicide attempts were associated with elevated depressive symptoms that improved over time. Pre-onset subthreshold psychotic symptoms were not associated with outcomes, except for a slightly different trajectory of functioning. Individuals with pre-onset self-harm or suicide attempts may benefit from early interventions that target their transsyndromic trajectories. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Psychopathological mediators between insecure attachment and psychotic features in a non-clinical sample: the role of depression and interpersonal sensitivity.

Attachment styles represent a personality pattern critical to psychological health, with insecure attachment being a central factor in developing psychopathological characteristics of psychosis. However, its downstream psychopathological pathways remain unclear. This study aimed to investigate the putative psychopathological mediators in the relationship between insecure attachment and psychotic features in a non-clinical sample of university students. We recruited two non-clinical samples for a total of 978 subjects, 324 males and 654 females, and administered the Relationship Questionnaire (RQ) to assess attachment styles and the Symptom Check-List 90 (SCL-90) to assess psychopathological symptoms. Moreover, the Paranoia and Psychoticism subscales of SCL-90 were combined and used as a measure of Psychosis (PSY). A mediation analysis model was carried out to establish the relationship among variables. Mediation analysis showed a total effect from RQ-Preoccupied and RQ-Fearful to PSY, respectively, 0.31 and 0.28. Direct effects from the SCL-90-R factor candidate mediator to PSY ranged from 0.51 for somatization to 0.72 for depression and 0.72 for interpersonal sensitivity. Indirect effects ranged from 0.08 for RQ-Preoccupied via hostility to 0.21 for RQ-Preoccupied via depression. Our results show that the effect of insecure attachment on psychosis features is differentially mediated by some psychopathological dimensions, being depression and interpersonal sensitivity the most relevant ones. PSY feature, therefore, is predicted by other specific symptoms in the psychological context of insecure primary relationships. From a preventive and clinical point of view, our results could be relevant in informing the early-stage psychological treatment of pre-psychotic states and, in general, people experiencing sub-threshold psychotic symptoms.

P498. Intact Implicit Reinforcement Learning in Schizophrenia and Youth at Clinical High-Risk for Psychosis

Negative symptoms (e.g., amotivation) are prominent in schizophrenia (SZ). These symptoms begin early in the course of the disorder, including in youth at clinical high-risk for psychosis (CHR) with subthreshold psychotic symptoms. In SZ, negative symptoms are linked to reward-based learning dysfunction. However, previous research suggests implicit reinforcement learning remains intact in SZ. It is unknown whether CHR individuals also have preserved implicit reinforcement learning, knowledge of which may help clarify mechanistic pathways of negative symptoms and psychosis risk.

Social recovery therapy for young people with emerging severe mental illness: the Prodigy RCT.

Young people with social disability and non-psychotic severe and complex mental health problems are an important group. Without intervention, their social problems can persist and have large economic and personal costs. Thus, more effective evidence-based interventions are needed. Social recovery therapy is an individual therapy incorporating cognitive-behavioural techniques to increase structured activity as guided by the participant's goals. This trial aimed to test whether or not social recovery therapy provided as an adjunct to enhanced standard care over 9 months is superior to enhanced standard care alone. Enhanced standard care aimed to provide an optimal combination of existing evidence-based interventions. A pragmatic, single-blind, superiority randomised controlled trial was conducted in three UK centres: Sussex, Manchester and East Anglia. Participants were aged 16-25 years with persistent social disability, defined as < 30 hours per week of structured activity with social impairment for at least 6 months. Additionally, participants had severe and complex mental health problems, defined as at-risk mental states for psychosis or non-psychotic severe and complex mental health problems indicated by a Global Assessment of Functioning score ≤ 50 persisting for ≥ 6 months. Two hundred and seventy participants were randomised 1 : 1 to either enhanced standard care plus social recovery therapy or enhanced standard care alone. The primary outcome was weekly hours spent in structured activity at 15 months post randomisation. Secondary outcomes included subthreshold psychotic, negative and mood symptoms. Outcomes were collected at 9 and 15 months post randomisation, with maintenance assessed at 24 months. The addition of social recovery therapy did not significantly increase weekly hours in structured activity at 15 months (primary outcome treatment effect -4.44, 95% confidence interval -10.19 to 1.31). We found no evidence of significant differences between conditions in secondary outcomes at 15 months: Social Anxiety Interaction Scale treatment effect -0.45, 95% confidence interval -4.84 to 3.95; Beck Depression Inventory-II treatment effect -0.32, 95% confidence interval -4.06 to 3.42; Comprehensive Assessment of At-Risk Mental States symptom severity 0.29, 95% confidence interval -4.35 to 4.94; or distress treatment effect 4.09, 95% confidence interval -3.52 to 11.70. Greater Comprehensive Assessment of At-Risk Mental States for psychosis scores reflect greater symptom severity. We found no evidence of significant differences at 9 or 24 months. Social recovery therapy was not estimated to be cost-effective. The key limitation was that missingness of data was consistently greater in the enhanced standard care-alone arm (9% primary outcome and 15% secondary outcome missingness of data) than in the social recovery therapy plus enhanced standard care arm (4% primary outcome and 9% secondary outcome missingness of data) at 15 months. We found no evidence for the clinical superiority or cost-effectiveness of social recovery therapy as an adjunct to enhanced standard care. Both arms made large improvements in primary and secondary outcomes. Enhanced standard care included a comprehensive combination of evidence-based pharmacological, psychotherapeutic and psychosocial interventions. Some results favoured enhanced standard care but the majority were not statistically significant. Future work should identify factors associated with the optimal delivery of the combinations of interventions that underpin better outcomes in this often-neglected clinical group. Current Controlled Trials ISRCTN47998710. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment Vol. 25, No. 70. See the NIHR Journals Library website for further project information.

Follow-up of subjects labelled with putative pre-psychotic states: Viewed from a transdiagnostic clinical high-at-risk mental state (CHARMS) paradigm

Follow-up of subjects with putative pre-psychotic states is essential to clarify the transition process to psychosis, while "non-converters" also deserve clinical attention as many may evolve into other psychiatric disorders with diverse outcomes. This study aimed to examine help-seeking individuals who have been labelled at clinical high-risk state but not converting to full-blown psychosis during first two years of follow-up. A retrospective observational cohort study of help-seeking subjects was conducted by reviewing medical records of participants in a previous early psychosis study at the study hospital between 2006 and 2020. We portrayed those who developed first episode psychosis after first 2-year follow-up in detail, and provided sketches of clinical macrophenotypes other than psychosis emerging from subjects among different risk groups. Among 132 eligible subjects, data of 98 (74.2%) were available for detailed evaluation. Of these, 15 transitioned to first-episode psychosis (11.4%) with time to psychosis from 2 to 11 years, 11 had anxiety spectrum (8.3%), 11 had depressive spectrum (8.3%), 10 had obsessive compulsive (7.6%), 5 had bipolar spectrum disorders (3.8%), 13 had predominantly schizotypal (9.8%) and 4 had other personality traits (3%), and 13 had problems attributable to adjustment or developmental issues (9.8%). Various diagnoses, either full- or sub-threshold, appropriately describe the diverse clinical phenomenology of a cohort presenting with non-specific and/or subthreshold psychotic symptoms. The clinical high-at-risk mental state (CHARMS) paradigm provides a reasonable transdiagnostic approach for orienting clinicians' attention toward young subjects seeking mental health help at an early stage of illness to potentially pluripotent trajectories.

Dynamic association of the first identifiable symptom with rapidity of progression to first-episode psychosis.

Rapid progression from the first identifiable symptom to the onset of first-episode psychosis (FEP) allows less time for early intervention. The aim of this study was to examine the association between the first identifiable symptom and the subsequent speed of illness progression. Data were available for 390 patients attending a catchment-based early intervention service for FEP. Exposure to non-psychotic and subthreshold psychotic symptoms was retrospectively recorded using semi-structured interviews. Outcomes following the onset of the first identifiable symptom were (1) time to onset of FEP and (2) symptom incidence rate (i.e. number of symptoms emerging per person-year until FEP onset). These outcomes were respectively analyzed with Cox proportional hazards and negative binomial regressions. After Bonferroni correction, having a subthreshold psychotic (v. non-psychotic) symptom as the first symptom was not associated with time to FEP onset [hazard ratio (HR) = 1.39; 95% CI 0.94-2.04] but was associated with higher symptom incidence [incidence rate ratio (IRR) = 1.92; 95% CI 1.10-3.48]. A first symptom of suspiciousness was associated with shorter time to FEP onset (HR = 2.37; 95% CI 1.38-4.08) and higher symptom incidence rate (IRR = 3.20; 95% CI 1.55-7.28) compared to other first symptoms. In contrast, a first symptom of self-harm was associated with lower symptom incidence rate (IRR = 0.06; 95% CI 0.01-0.73) compared to other first symptoms. Several associations between symptoms and illness progression were moderated by the age at symptom onset. Appreciating the content and timing of early symptoms can identify windows and treatment targets for early interventions in psychosis.

Obsessive-compulsive symptoms in schizophrenia patients and their first-degree relatives and the association with subclinical psychotic symptoms

Objective This study aimed to investigate the presence of obsessive-compulsive symptoms (OCS) in patients being followed for schizophrenia and their first-degree relatives (mother, father, siblings, and children) and the relationship between OCS and clinical/subclinical psychotic symptoms. Materials and methods The study included 110 schizophrenia patients followed up in a community mental health center and their first-degree relatives. Patients and relatives were evaluated using the SCID-I (Structured Clinical Interview Form for DSM-IV Axis-I Disorders) to ascertain their diagnosis and exclude other axis-I diagnoses. The Yale-Brown Obsessive Compulsive Scale was used to measure OCS severity. Psychotic symptom severity was evaluated in patients using the Positive and Negative Syndrome Scale (PANSS) and subthreshold psychotic symptoms and psychosis proneness were assessed in relatives using the Schizotypal Personality Questionnaire. Results The prevalence of clinically significant OCS was 41.8% in schizophrenia patients and 28.2% in their relatives. PANSS positive and general psychopathology subscale scores were higher in patients with OCS. Suspiciousness and interpersonal schizotypy scores were significantly higher in relatives with OCS compared to those without. The first-degree relatives of patients with OCS did not exhibit a higher prevalence of OCS or psychotic symptoms compared to the relatives of patients without OCS. Conclusion Our study demonstrates that obsessive-compulsive phenomena are common in schizophrenia patients and their relatives. Although there seems to be a positive association between OCS and psychotic symptoms in patients and their first-degree relatives, the intergenerational transmission of these two symptom groups may occur independently.

Brain volume in chronic ketamine users — relationship to sub-threshold psychotic symptoms and relevance to schizophrenia

RationaleKetamine may model aspects of schizophrenia arising through NMDA receptor activity deficits. Although acute ketamine can induce effects resembling both positive and negative psychotic symptoms, chronic use may be a closer model of idiopathic psychosis.ObjectivesWe tested the hypotheses that ketamine users had lower brain volumes, as measured using MRI, and greater sub-threshold psychotic symptoms relative to a poly-drug user control group.MethodsKetamine users (n = 17) and poly-drug using controls (n = 19) were included in the study. All underwent volumetric MRI imaging and measurement of sub-threshold psychotic symptoms using the Comprehensive Assessment of At-Risk Mental State (CAARMS). Freesurfer was used to analyse differences in regional brain volume, cortical surface area and thickness between ketamine users and controls. The relationship between CAARMS ratings and brain volume was also investigated in ketamine users.ResultsKetamine users were found to have significantly lower grey matter volumes of the nucleus accumbens, caudate nucleus, cerebellum and total cortex (FDR p < 0.05; Cohen’s d = 0.36–0.75). Within the cortex, ketamine users had significantly lower grey matter volumes within the frontal, temporal and parietal cortices (Cohen’s d 0.7–1.31; FDR p < 0.05). They also had significantly higher sub-threshold psychotic symptoms (p < 0.05). Frequency of ketamine use showed an inverse correlation with cerebellar volume (p < 0.001), but there was no relationship between regional brain volumes and sub-threshold psychotic symptoms.ConclusionsChronic ketamine use may cause lower grey matter volumes as well as inducing sub-threshold psychotic symptoms, although these likely arise through distinct mechanisms.

Cannabidiol for at risk for psychosis youth: A randomized controlled trial.

No biological treatment has been firmly established for the at-risk stage of psychotic disorder. In this study we aim to test if subthreshold psychotic symptoms can be effectively treated with cannabidiol (CBD), a non-psychoactive compound of the plant Cannabis sativa. The question has taken on increased importance in the wake of evidence questioning both the need and efficacy of specific pharmacological interventions in the ultra-high risk (UHR) for psychosis group. Three-arm randomized controlled trial of 405 patients (135 per arm) aged 12-25 years who meet UHR for psychosis criteria. The study includes a 6-week lead-in phase during which 10% of UHR individuals are expected to experience symptom remission. Participants will receive CBD (per oral) at doses 600 or 1000 mg per day (fixed schedule) for 12 weeks. Participants in the third arm of the trial will receive matching placebo capsules. Primary outcome is severity of positive psychotic symptoms as measured by the Comprehensive Assessment of At-Risk Mental States at 12 weeks. We hypothesize that CBD will be significantly more effective than placebo in improving positive psychotic symptoms in UHR patients. All participants will also be followed up 6months post baseline to evaluate if treatment effects are sustained. This paper reports on the rationale and protocol of the Cannabidiol for At Risk for psychosis Youth (CanARY) study. This study will test CBD for the first time in the UHR phase of psychotic disorder.

Inter-rater reliability of subthreshold psychotic symptoms in individuals with 22q11.2 deletion syndrome

BackgroundPathways leading to psychosis in 22q11.2 deletion syndrome (22q11.2DS) have been the focus of intensive research during the last two decades. One of the common clinical risk factors for the evolution of psychosis in 22q11.2DS is the presence of positive and negative subthreshold psychotic symptoms. The gold standard for measuring subthreshold symptoms is the Structured Interview for Prodromal Syndromes (SIPS) and its accompanying Scale of Prodromal Symptoms (SOPS) ratings. Although the scale has been used by many centers studying 22q11.2DS, the inter-site reliability of the scale in this population has never been established.MethodsIn the present study, experienced clinical assessors from three large international centers studying 22q11.2DS independently rated video recordings of 18 adolescents and young adults with 22q11.2DS.ResultsThe intraclass correlations coefficients (ICCs) among three raters for the SOPS total scores, as well as for the positive, negative, and disorganization subscale scores, were good-to-excellent (ICCs range 0.73–0.93). The raters were also able to reliably determine the subjects’ subthreshold syndrome status (ICC = 0.71). The reliability of individual items was good-to-excellent for all items, ranging from 0.61 for motor disturbances [G3] to 0.95 for bizarre thinking.ConclusionsOur results show that trained clinicians can reliably screen for subthreshold psychotic symptoms in individuals with 22q11.2DS. To increase assessment reliability, we suggest specific clarifications and simplifications to the standard SIPS interview for future studies.

Structural Cerebellar Correlates of Psychotic and Sub-Threshold Psychotic Symptoms in the 3q29 Deletion Syndrome

The 3q29 deletion is a recurrent copy number variant (CNV) that confers a ∼40-fold increased risk for schizophrenia (SZ), the largest known effect size for any SZ-associated genetic variant. Recent findings by the Emory 3q29 Project (http://genome.emory.edu/3q29/) revealed that cerebellar hypoplasia is a common feature of 3q29 deletion syndrome (3q29DS). This is coincident with emerging SZ literature implicating the cerebellum as a central site of neuropathology. We investigated the relationship between cerebellar volume and psychotic and sub-threshold psychotic symptoms in 3q29DS.

Individualized risk components guiding antipsychotic delivery in patients with a clinical high risk of psychosis: application of a risk calculator.

Antipsychotics are widely used for treating patients with psychosis, and target threshold psychotic symptoms. Individuals at clinical high risk (CHR) for psychosis are characterized by subthreshold psychotic symptoms. It is currently unclear who might benefit from antipsychotic treatment. Our objective was to apply a risk calculator (RC) to identify people that would benefit from antipsychotics. Drawing on 400 CHR individuals recruited between 2011 and 2016, 208 individuals who received antipsychotic treatment were included. Clinical and cognitive variables were entered into an individualized RC for psychosis; personal risk was estimated and 4 risk components (negative symptoms-RC-NS, general function-RC-GF, cognitive performance-RC-CP, and positive symptoms-RC-PS) were constructed. The sample was further stratified according to the risk level. Higher risk was defined based on the estimated risk score (20% or higher). In total, 208 CHR individuals received daily antipsychotic treatment of an olanzapine-equivalent dose of 8.7 mg with a mean administration duration of 58.4 weeks. Of these, 39 (18.8%) developed psychosis within 2 years. A new index of factors ratio (FR), which was derived from the ratio of RC-PS plus RC-GF to RC-NS plus RC-CP, was generated. In the higher-risk group, as FR increased, the conversion rate decreased. A small group (15%) of CHR individuals at higher-risk and an FR >1 benefitted from the antipsychotic treatment. Through applying a personal risk assessment, the administration of antipsychotics should be limited to CHR individuals with predominantly positive symptoms and related function decline. A strict antipsychotic prescription strategy should be introduced to reduce inappropriate use.

Dysmaturation Observed as Altered Hippocampal Functional Connectivity at Rest Is Associated With the Emergence of Positive Psychotic Symptoms in Patients With 22q11 Deletion Syndrome

BackgroundHippocampal alterations are among the most replicated neuroimaging findings across the psychosis spectrum. Moreover, there is strong translational evidence that preserving the maturation of hippocampal networks in mice models prevents the progression of cognitive deficits. However, the developmental trajectory of hippocampal functional connectivity (HFC) and its contribution to psychosis is not well characterized in the human population. 22q11 deletion syndrome (22q11DS) offers a unique model for characterizing early neural correlates of schizophrenia. MethodsWe acquired resting-state functional magnetic resonance imaging in 242 longitudinally repeated scans from 84 patients with 22q11DS (30 with moderate to severe positive psychotic symptoms) and 94 healthy control subjects in the age span of 6 to 32 years. We obtained bilateral hippocampus to whole-brain functional connectivity and employed a novel longitudinal multivariate approach by means of partial least squares correlation to evaluate the developmental trajectory of HFC across groups. ResultsRelative to control subjects, patients with 22q11DS failed to increase HFC with frontal regions such as the dorsal part of the anterior cingulate cortex, prefrontal cortex, and supplementary motor area. Concurrently, carriers of the deletion had abnormally higher HFC with subcortical dopaminergic areas. Remarkably, this aberrant maturation of HFC was more prominent during midadolescence and was mainly driven by patients exhibiting subthreshold positive psychotic symptoms. ConclusionsOur findings suggest a critical period of prefrontal cortex–hippocampal–striatal circuit dysmaturation, particularly during late adolescence, which in light of current translation evidence could be a target for short-term interventions to potentially achieve long-lasting rescue of circuit dysfunctions associated with psychosis.