Risk For Psychosis Research Articles

Neuroticism and Extraversion are modifiable by treatment in individuals at-risk for psychosis or with first-episode psychotic disorder

Meta-analytic work suggests that Neuroticism and Extraversion levels are modifiable by treatment, but it is unknown whether this holds for individuals with subclinical or clinical psychosis. The current study aimed to examine whether 1) Neuroticism and Extraversion change through intervention in individuals at clinical high risk for psychosis (CHR) or first-episode psychosis (FEP), and 2) Acceptance and Commitment Therapy in Daily Life (ACT-DL) is more successful in this regard compared to treatment as usual (TAU). Data pertain to the INTERACT study, a randomized controlled trial on the efficacy of ACT-DL in individuals with CHR or FEP. Assessments were at baseline, 8 week post-intervention and 6 and 12-month follow-up. Our sample consisted of 142 participants (ACT-DL: 67 and TAU: 75). Mixed model analyses showed a reduction in Neuroticism at post-intervention and both follow-up. Extraversion increased at 6 month follow-up. There was no difference between ACT-DL and TAU in personality change. Analyses were controlled for clinical group status (CHR vs. FEP), gender, age, IQ, baseline personality levels and baseline symptom levels. Our findings suggest that among help-seeking people at-risk for psychosis or with first-episode psychosis, treatment may have a fast and persistent impact on particularly Neuroticism. Potential mechanisms are discussed.

Perspective on clinical high-risk for psychosis in Africa.

Clinical High Risk for Psychosis has evolved in recent years as a conceptual and clinical entity, representing a shift in focus from the syndromal psychosis state to a recognition of the pre-psychotic state as a period of potential preventive intervention. Much existing evidence has been generated from well-resourced countries, with a more limited body of literature available from Africa and other Majority World countries. Against a backdrop of prevailing systemic challenges, it is necessary to appraise the state of knowledge on Clinical High Risk for Psychosis in Africa. In this perspective article, we cover epidemiology, risk factors, predictors of psychosis conversion, as well as an overview of sociocultural factors, notably stigma, and the barriers to mental health services in African settings. We discuss existing and promising assessment approaches and reflect on preventive and early intervention strategies. We conclude with recommendations including the need for more clinical, longitudinal, and collaborative research anchored in an integrative transdisciplinary approach. We highlight the need for more culturally valid assessment tools and strategies to improve access to and utilization of services while also reducing stigma.

Eligibility of emergency psychiatry patients for clinical trials studying depression

BackgroundDifferences often exist between people with depression who are eligible for clinical trials and those seen in clinical practice. The impact of exclusion criteria on eligibility has been previously reported for inpatients and outpatients, but has not been assessed for emergency psychiatry patients; a group that overlaps with inpatients and outpatients but also has important distinctives. Understanding the frequencies of commonly used exclusion criteria in this population could inform interpretation of existing data (generalizability) and highlight opportunities/needs for future trials. MethodsWe reviewed 67 clinical trials studying depression using Qualitative Content Analysis to identify common and recurring exclusion criteria. We examined the frequency of these exclusion criteria among a clinical sample of emergency psychiatry patients. ResultsMost clinical trials had exclusions for basic research requirements, age, symptom severity, psychosis, and substance use. Applying 9 commonly used exclusion criteria to the clinical population resulted in a 3.3 % eligibility rate (95 % CI 1.2 %–7.0 %). Exclusions for psychosis (85.1 % of trials), substance use (83.6 % of trials), and suicide risk (65.7 % of trials) would likely exclude 93 % of emergency psychiatry patients. The prevalence of psychosis, substance use, and suicide risk was much higher among emergency psychiatry patients than among previously studied populations. LimitationsSome eligibility criteria could not be measured. The Qualitative Content Analysis consolidated similar exclusion criteria, losing potentially important nuances in wordings. ConclusionsExclusion criteria commonly used in contemporary clinical trials of depression limit generalizability to emergency psychiatry patients, due in large part to exclusions for psychosis, substance use, and suicide risk.

Brain health in ethnically minority youth at risk for psychosis.

Brain health in ethnically minority youth at risk for psychosis.

Evaluation of a new intrinsic and extrinsic motivation scale in youth with psychosis spectrum symptoms

BackgroundImpairment in intrinsic motivation (IM), the drive to satisfy internal desires like mastery, may play a key role in disability in psychosis. However, we have limited knowledge regarding relative impairments in IM compared to extrinsic motivation (EM) or general motivation (GM), in part due to limitations in existing measures. MethodsHere we address this gap using a novel Trait Intrinsic and Extrinsic Motivation self-report scale in a sample of n = 243 participants including those with schizophrenia, psychosis-risk, and healthy controls. Each of the 7 IM and 6 EM items used a 7-point Likert scale assessing endorsement of dispositional statements. Bifactor analyses of these items yielded distinct IM, EM, and GM factor scores. Convergent and discriminant validity were examined in relation to General Causality Orientation Scale (GCOS-CP) and Quality of Life 3-item IM measure (QLS-IM). Utility was assessed in relation to psychosis-spectrum (PS) status and CAINS clinical amotivation. ResultsIM and EM showed acceptable inter-item consistency (IM: α = 0.88; EM: α = 0.66); the bifactor model exhibited fit that varied from good to borderline to inadequate depending on the specific fit metric (SRMR = 0.038, CFI = 0.94, RMSEA = 0.106 ± 0.014). IM scores correlated with established IM measures: GCOS-CP Autonomy (rho = 0.38, p < 0.01) and QLS-IM (rho = 0.29, p < 0.01). Supporting discriminant validity, IM did not correlate with GCOS-CP Control (rho = −0.14, p > 0.05). Two-year stability in an available longitudinal subset (n = 35) was strong (IM: rho = 0.64, p < 0.01; EM: rho = 0.55, p < 0.01). Trait IM was lower in PS youth (t = 4.24, p < 0.01), and correlated with clinical amotivation (rho = −0.36, p < 0.01); EM did not show significant clinical associations. ConclusionsThese results demonstrate the clinical relevance of IM in psychosis risk. They also provide preliminary support for the reliability, validity and utility of this new Trait IM-EM scale, which addresses a measurement gap and can facilitate identification of neurobehavioral and clinical correlates of IM deficits.

The SPEAK study rationale and design: A linguistic corpus-based approach to understanding thought disorder.

Psychotic symptoms are typically measured using clinical ratings, but more objective and sensitive metrics are needed. Hence, we will assess thought disorder using the Research Domain Criteria (RDoC) heuristic for language production, and its recommended paradigm of "linguistic corpus-based analyses of language output". Positive thought disorder (e.g., tangentiality and derailment) can be assessed using word-embedding approaches that assess semantic coherence, whereas negative thought disorder (e.g., concreteness, poverty of speech) can be assessed using part-of-speech (POS) tagging to assess syntactic complexity. We aim to establish convergent validity of automated linguistic metrics with clinical ratings, assess normative demographic variance, determine cognitive and functional correlates, and replicate their predictive power for psychosis transition among at-risk youths. This study will assess language production in 450 English-speaking individuals in Australia and Canada, who have recent onset psychosis, are at clinical high risk (CHR) for psychosis, or who are healthy volunteers, all well-characterized for cognition, function and symptoms. Speech will be elicited using open-ended interviews. Audio files will be transcribed and preprocessed for automated natural language processing (NLP) analyses of coherence and complexity. Data analyses include canonical correlation, multivariate linear regression with regularization, and machine-learning classification of group status and psychosis outcome. This prospective study aims to characterize language disturbance across stages of psychosis using computational approaches, including psychometric properties, normative variance and clinical correlates, important for biomarker development. SPEAK will create a large archive of language data available to other investigators, a rich resource for the field.

The ethnic density effect as a contextual influence in ecological disease models: Establishing its quantitative expression.

Research suggests higher neighbourhood ethnic minority density to be associated with lessened chances of ethnic group illness. We focus on the density effect on psychosis, arguing that (at higher ethnic concentrations) it acts as a contextual influence attenuating the compositional influence whereby minority ethnicity is associated with higher psychosis risk. In terms of ecological disease regression, the ethnic density effect will then be apparent in nonlinear impacts of minority concentration. Contextual effects may also be evident in spatially varying regression coefficient models for psychosis. Nonlinearity or heterogeneity may be associated with other contextual processes where geography modifies demography (e.g. deprivation amplification). We illustrate these issues with an analysis of psychosis prevalence in 4835 London neighbourhoods. The data are collected in primary care (during 2019/20) using clinical diagnosis (e.g. based on referrals to specialists or psychosis hospitalisation), and refer to patients currently under care: such care may extend retrospectively over several years. The data offer a complete population perspective in contrast to survey data, which typically offer limited geographic perspectives. We consider impacts on psychosis prevalence of non-white ethnicity, as well as those of deprivation, social fragmentation and urbanicity. We find evidence suggesting nonlinear impacts of non-white ethnicity on psychosis (essentially flat risk above a threshold concentration), but find no evidence for deprivation amplification.

Age-related change in cortical thickness in adolescents at clinical high risk for psychosis: a longitudinal study.

Progression to psychosis has been associated with increased cortical thinning in the frontal, temporal and parietal lobes in individuals at clinical high risk for the disorder (CHR-P). The timing and spatial extent of these changes are thought to be influenced by age. However, most evidence so far stems from adult samples. Longitudinal studies are essential to understanding the neuroanatomical changes associated to transition to psychosis during adolescence, and their relationship with age. We conducted a longitudinal, multisite study including adolescents at CHR-P and healthy controls (HC), aged 10-17years. Structural images were acquired at baseline and at 18-month follow-up. Images were processed with the longitudinal pipeline in FreeSurfer. We used a longitudinal two-stage model to compute the regional cortical thickness (CT) change, and analyze between-group differences controlling for age, sex and scan, and corrected for multiple comparisons. Linear regression was used to study the effect of age at baseline. A total of 103 individuals (49 CHR-P and 54 HC) were included in the analysis. During follow-up, the 13 CHR-P participants who transitioned to psychosis exhibited greater CT decrease over time in the right parietal cortex compared to those who did not transition to psychosis and to HC. Age at baseline correlated with longitudinal changes in CT, with younger individuals showing greater cortical thinning in this region. The emergence of psychosis during early adolescence may have an impact on typical neuromaturational processes. This study provides new insights on the cortical changes taking place prior to illness onset.

Environmental factors contributing to negative symptoms in youth at clinical high risk for psychosis and outpatients with schizophrenia.

A bioecosystem theory was recently proposed positing that negative symptoms of schizophrenia (SZ) are influenced by environmental factors. These environmental processes reflect sources of resource deprivation that manifest across multiple systems that impact individuals directly through microsystems and indirectly through the exosystem and macrosystem. As an initial test of this theory, the current study examined whether self-reported environmental resource deprivation was associated with anhedonia, avolition, and asociality. Two samples were collected: (1) outpatients with schizophrenia or schizoaffective disorder (SZ: n = 38) and matched psychiatrically heathy controls (CN: n = 31); (2) youth at clinical high risk for psychosis (CHR: n = 34) and matched CN (n = 30). Measures of negative symptoms and environmental factors influencing the frequency of recreational, goal-directed, and social activities were collected. Negative symptoms were associated with environmental deprivation factors in the microsystem (number of social and activity settings) and exosystem (economy, mass media, politics/laws, neighborhood crime). These associations did not appear due to depression and were greater among those with SZ than CHR. These findings provide preliminary support for the bioecosystem theory and highlight an under-recognized role for environmental factors underlying negative symptoms across phases of psychotic illness. Environmental systems-focused treatment approaches may offer a novel means of treating negative symptoms, which could be promising when coupled with person-level pharmacological and psychosocial treatments.

116 Differential complement iC3b levels in baseline plasma of individuals at clinical high risk for psychosis

116 Differential complement iC3b levels in baseline plasma of individuals at clinical high risk for psychosis

Study of Relationship between Stool Lactobacillus acidophilus and Grave’s Disease in a Sample of Egyptian Population

Abstract Background Graves’ disease is an autoimmune disease that leads to a generalized overactivity of the entire thyroid gland (hyperthyroidism). When unrecognized, It impacts negatively on quality of life and poses serious risks of psychosis, tachyarrhythmia and cardiac failure. It affect 0.5% of the population in the US, and represents 50-80% of cases of hyperthyroidism. It occurs more commonly amongst women, smokers and patients with other autoimmune diseases or a family history of thyroid autoimmunity. Aim of the Work The study is aimed to study the relationship between stool lactobacillus acidophilus and grave’s disease in a sample of Egyptian population Patients and Methods This study is a case control study, was carried out at Endocrine outpatient clinic at Ain Shams University Hospital, on 60 Egyptian patients age 25-40 years old, from September 2020 till March 2021. Results Among group1A, 5(25%) were 25 -30 years old, 6(30%) were 30 – 35 years old, 9(45%) were ≥ 35 years old, the mean of ages was 32.75 (±4.94 SD) with range (25.0 – 40.0), there were 5(25%) males, 15(75%) females, the mean of duration of the disease was 2.95(±2.14 SD) with range (1.0 – 7.0). Among group 1B, 8(40%) were 25 -30 years old, 5(25%) were 30 – 35 years old, 7(35%) were ≥ 35 years old, the mean of ages was 31.90(±4.69 SD) with range (26.0 – 40.0), there were 3(15%) males, 17(85%) females, the mean of duration of the disease was 3.25(±2.02 SD) with range (1.0 – 7.0). Among total cases of group 1, 13(32%) were 25 -30 years old, 11(27.5%) were 30 – 35 years old, 16(40%) were ≥ 35 years old, the mean of ages was 32.33(±4.77 SD) with range (25.0 – 40.0), there were 8(20%) males, 32(80%) females, the mean of duration of the disease was 3.10 (±2.06 SD) with range (1.0 – 7.0). Conclusion Stool Lactobacillus acidophilus PCR count was insignificantly different between studied groups, which may show no relationship of lactobacillus with graves’ disease. so, further studies are needed to determine correlation or causation of this relationship.

Oxytocin as a treatment for high-risk psychosis or early stages of psychosis: a mini review.

Individuals at clinical high risk for psychosis (CHR-P) present as help-seeking individuals with social deficits as well as cognitive and functional impairment and have a 23-36% risk of transition to first-episode psychosis. The therapeutic role of intranasal oxytocin (ΟΤ) in psychiatric disorders has been widely studied during the last decades, concerning its effects on social behavior in humans. A literature search was conducted via Pubmed and Scopus, using the search terms "oxytocin" and "psychosis." Six studies were included in the current review. There were differences in terms of demographics, intervention type, and outcome measures. ΟΤ may affect the social cognition skills of people at prodromal and early stages of psychosis, but its effect on clinical symptoms is ambiguous. Because of the high level of heterogeneity of existing studies, more original studies are needed to examine and clarify whether OT improves high-risk and early psychosis populations.

Association of Childhood Area-Level Ethnic Density and Psychosis Risk Among Ethnoracial Minoritized Individuals in the US

The protective ethnic density effect hypothesis, which suggests that minoritized individuals who grow up in neighborhoods with a high proportion of ethnoracial minoritized groups are protected from the effects of perceived discrimination, has not been examined among individuals at clinical high risk of psychosis (CHR-P). This level of examination may help identify intervention targets for preventing psychosis among high-risk individuals. To examine the association between area-level ethnic density during childhood, perceived discrimination, and psychosis risk outcomes among ethnoracial minoritized individuals with CHR-P. Data were collected as part of the North American Prodrome Longitudinal Study-2 (NAPLS 2) between November 2008 and March 2013. Participants included ethnoracial minoritized youth with CHR-P. Area-level ethnoracial minoritized density pertained to the percent of ethnoracial minoritized individuals within the participant's county during childhood. Generalized mixed-effects models with random intercepts for participants, NAPLS 2 site, and county estimated the associations between area-level ethnic density and the risk of psychosis risk outcomes. Self-reported experience of discrimination was assessed. Mediation analyses computed the indirect association of perceived discrimination in the prospective correlation between ethnic density and psychosis risk outcomes. Analyses took place between December 2021 and June 2023. Psychosis risk outcomes included remission, symptomatic, progression, and conversion to psychosis and were assessed throughout 24-month follow-up. Of 193 individuals, the mean (SD) age was 17.5 (3.4) years and 113 males (58.5%) were included. Participants self-identified as Asian (29 [15.0%]), Black (57 [29.0%]), Hispanic (any race; 87 [45.0%]), or other (First Nations, Middle Eastern, and interracial individuals; 20 [10.4%]). Greater area-level minoritized density was associated with a lower likelihood of remaining symptomatic (relative risk [RR], 0.54 [95% CI, 0.33-0.89]) and having progressively worsening symptoms (RR, 0.52 [95% CI, 0.32-0.86]) compared with being in remission. More perceived discrimination was associated with a higher risk of staying symptomatic (RR, 1.43 [95% CI, 1.09-1.88]) and progressively worsening (RR, 1.34 [95% CI, 1.02-1.78]) compared with being in remission. Perceived discrimination significantly mediated 21.7% (95% CI, 4.1%-67.0%; P = .02) of the association between area-level minoritized density and the likelihood of being in remission. This study found that among ethnoracial minority youth with CHR-P, growing up in communities with a greater proportion of ethnically minoritized individuals was associated with remission of psychosis risk symptoms partly through lower levels of perceived discrimination. Understanding how the social environment impacts early psychosis risk may help develop effective interventions to prevent psychosis, especially for vulnerable minoritized youth.

Recreational cannabis use over time in individuals at clinical high risk for psychosis: Lack of associations with symptom, neurocognitive, functioning, and treatment patterns

Recreational cannabis use has recently gained considerable interest as an environmental risk factor that triggers the onset of psychosis. To date, however, the evidence that cannabis is associated with negative outcomes in individuals at clinical high risk (CHR) for psychosis is inconsistent. The present study tracked cannabis usage over a 2-year period and examined its associations with clinical and neurocognitive outcomes, along with medication rates. CHR youth who continuously used cannabis had higher neurocognition and social functioning over time, and decreased medication usage, relative to non-users. Surprisingly, clinical symptoms improved over time despite the medication decreases.

Personality functioning and self-disorders in individuals at ultra-high risk for psychosis, with first-episode psychosis and with borderline personality disorder.

Assessment of personality functioning in different stages of psychotic disorders could provide valuable information on psychopathology, course of illness and treatment planning, but empirical data are sparse. To investigate personality functioning and sense of self in individuals at ultra-high risk (UHR) for psychosis and with first-episode psychosis (FEP) in comparison with a clinical control group of individuals with borderline personality disorder (BPD) and healthy controls. In a cross-sectional design, we investigated personality functioning (Structured Interview of Personality Organization, STIPO; Level of Personality Functioning Scale, LPFS) and disturbances of the basic self (Examination of Anomalous Self-Experience, EASE) in 107 participants, comprising 24 individuals at UHR, 29 individuals with FEP, 27 individuals with BPD and 27 healthy controls. The UHR, FEP and BPD groups had moderate to severe deficits in personality organisation (STIPO) compared with the healthy control group. Self-functioning with its subdomain (facet) 'self-direction' (LPFS) was significantly worse in participants with manifest psychosis (FEP) compared with those at-risk for psychosis (UHR). The FEP group showed significantly worse overall personality functioning than the UHR group and significantly higher levels of self-disturbance (EASE) than the BPD group, with the UHR group lying between these diagnostic groups. Hierarchical cluster analysis based on the seven STIPO domains yielded three clusters differing in level of personality functioning and self-disturbances. Our data demonstrate that psychotic disorders are associated with impaired personality functioning and self-disturbances. Assessment of personality functioning can inform treatment planning for patients at different stages of psychotic disorder.

Suicide risk among individuals at Ultra-High Risk (UHR) of psychosis in a developing North African country: A 12-month naturalistic prospective cohort study from the TRIP project

BackgroundThe limited studies that focused on suicidality in individuals at Ultra-High Risk (UHR) of psychosis were predominantly cross-sectional, emerging from Western countries. We aimed to examine suicide risk among Tunisian UHR and First Episode Psychosis (FEP) patients at baseline, and to evaluate the evolution and correlates of suicidal ideation over a 12-month period in the UHR group exclusively. Methods35 UHR (aged 22.8 ± 4.0 years, 45.7% male) and 33 FEP (aged 27.3 ± 4.8 years, 63.6% male) participants were included. The Comprehensive Assessment of at Risk Mental States, the Positive and Negative Syndrome Scale (PANSS), The Rosenberg Self-Esteem Scale, and The Multidimensional Scale of Perceived Social Support were used. ResultsNo significant differences were found between the UHR and the FEP groups with regard to levels of suicidal ideation at baseline. Suicidal ideation scores showed a significant decrease over time in UHR participants (p=.014; η2=0.242). An increase in total PANSS scores at 1 year (Beta=0.03; p=.048; 95%CI 0.001, 0.060; η2=0.182) significantly increased suicidal ideation scores at 1 year in the UHR group. ConclusionOur findings contribute to the limited body of evidence on this topic by providing new prospective data from a population, country and region that has never been researched previously.

A targeted psychological treatment for sleep problems in young people at ultra-high risk of psychosis in England (SleepWell): a parallel group, single-blind, randomised controlled feasibility trial

Sleep disturbance is common and problematic for young people at ultra-high risk of psychosis. Sleep disruption is a contributory causal factor in the occurrence of mental health problems, including psychotic experiences, anxiety, and depression. The implication is that treating sleep problems might have additional benefits on mental health outcomes in individuals at high risk. The present study had two aims: first, to establish the feasibility and acceptability of a randomised controlled trial to treat sleep problems with the aim of reducing psychotic experiences in young people at ultra-high risk of psychosis; and second, to provide proof of concept of the clinical efficacy of the treatment. We did a parallel group, single-blind, randomised controlled feasibility trial in two National Health Service trusts in England. Eligible participants were aged 14-25 years, a patient of mental health services, assessed as being at ultra-high risk of psychosis on the Comprehensive Assessment of At-Risk Mental States, and having current sleep problems (score of ≥15 on the self-report Insomnia Severity Index [ISI]). Participants were randomly assigned (1:1) to either a targeted psychological therapy for sleep problems (SleepWell) plus usual care or usual care alone via an automated online system, with non-deterministic minimisation that balanced participants for ISI score and referring service. The SleepWell therapy was delivered on an individual basis in approximately eight 1-h sessions over 12 weeks. Assessments were done at 0, 3, and 9 months, with trial assessors masked to treatment allocation. The key feasibility outcomes were the numbers of patients identified, recruited, and retained, treatment uptake, and data completion. Treatment acceptability was measured with the Abbreviated Acceptability Rating Profile (AARP). In preliminary clinical assessments, the primary clinical outcome was insomnia at 3 and 9 months assessed with the ISI, reported by randomised group (intention-to-treat analysis). Safety was assessed in all randomly assigned participants. The trial was prospectively registered on ISRCTN, 85601537, and is completed. From Nov 18, 2020, to Jan 26, 2022, 67 young people were screened, of whom 40 (60%) at ultra-high risk of psychosis were recruited. Mean age was 16·9 years (SD 2·5; range 14-23), and most participants identified as female (n=19 [48%]) or male (n=19 [48%]) and as White (n=32 [80%]). 21 participants were randomly assigned to SleepWell therapy plus usual care and 19 to usual care alone. All participants provided data on at least one follow-up visit. 39 (98%) of 40 participants completed the primary outcome assessment at 3 and 9 months. 20 (95%) of 21 participants assigned to SleepWell therapy received the prespecified minimum treatment dose of at least four sessions. The median treatment acceptability score on the AARP was 48 (IQR 46 to 48; n=17; maximum possible score 48). At the post-intervention follow-up (3 months), compared with the usual care alone group, the SleepWell therapy group had a reduction in insomnia severity (ISI adjusted mean difference -8·12 [95% CI -11·60 to -4·63]; Cohen's d=-2·67 [95% CI -3·81 to -1·52]), which was sustained at 9 months (ISI adjusted mean difference -5·83 [-9·31 to -2·35]; Cohen's d=-1·91 [-3·06 to -0·77]). Among the 40 participants, eight adverse events were reported in six participants (two [11%] participants in the usual care group and four [19%] participants in the SleepWell therapy group). One serious adverse event involving hospital admission for a physical health problem was reported in the SleepWell therapy group, and one patient in the usual care alone group transitioned to psychosis. None of these events were classed as being related to trial treatment or procedures. A randomised controlled trial of a targeted psychological sleep therapy for young people at ultra-high risk of psychosis is feasible. Patients can be retained in the trial and assessments done by masked assessors. Uptake of the sleep therapy was high, and we found preliminary evidence of sustained reductions in sleep problems. A definitive multicentre trial is now needed. NIHR Research for Patient Benefit and NIHR Oxford Health Biomedical Research Centre.

The risk of psychosis for transgender individuals: a Dutch national cohort study.

The stressful minority position of transgender persons may result in a high risk of psychosis. Conflicting data suggest that the observed risk depends on setting of recruitment. We assessed the relative risk of non-affective psychotic disorder (NAPD) in a large, representative cohort of transgender persons. This cohort was composed using: data on legal sex change from the Dutch population registry and data on dispensing of cross-sex hormones (route 1), and a registry of insurance claims from mental health care including persons with a diagnosis of gender identity disorder (DSM-IV) or gender dysphoria (DSM-5) (route 2). They were matched by sex at birth, calendar year and country of birth to controls from the general population. Transgender persons (N = 5564) and controls (N = 27 820), aged 16-60 years at 1 January 2011, were followed until the first insurance claim for NAPD in 2011-2019. The incidence rate ratio (IRR) of NAPD for transgender persons selected exclusively through route 1 (N = 3859, IRR = 2.00, 95%-CI 1.52-2.63) was increased, but significantly lower than the IRRs for those selected exclusively through route 2 (N = 694, IRR = 22.15, 95%-CI 13.91-35.28) and for those found by both routes (N = 1011, IRR = 5.17, 95%-CI 3.57-7.49; p value for differences in IRR < 0.001). This study supports the social defeat-hypothesis of NAPD. The results also show the presence of a substantial number of transgender persons with severe psychiatric problems who have not (yet) taken steps to gender-affirmative care.

The psychosis risk factor RBM12 encodes a novel repressor of GPCR/cAMP signal transduction

RBM12 is a high-penetrance risk factor for familial schizophrenia and psychosis, yet its precise cellular functions and the pathways to which it belongs are not known. We utilize two complementary models, HEK293cells and human iPSC-derived neurons, and delineate RBM12 as a novel repressor of the G protein-coupled receptor/cAMP/PKA (GPCR/cAMP/PKA) signaling axis. We establish that loss of RBM12 leads to hyperactive cAMP production and increased PKA activity as well as altered neuronal transcriptional responses to GPCR stimulation. Notably, the cAMP and transcriptional signaling steps are subject to discrete RBM12-dependent regulation. We further demonstrate that the two RBM12 truncating variants linked to familial psychosis impact this interplay, as the mutants fail to rescue GPCR/cAMP signaling hyperactivity in cells depleted of RBM12. Lastly, we present a mechanism underlying the impaired signaling phenotypes. In agreement with its activity as an RNA-binding protein, loss of RBM12 leads to altered gene expression, including that of multiple effectors of established significance within the receptor pathway. Specifically, the abundance of adenylyl cyclases, phosphodiesterase isoforms, and PKA regulatory and catalytic subunits is impacted by RBM12 depletion. We note that these expression changes are fully consistent with the entire gamut of hyperactive signaling outputs. In summary, the current study identifies a previously unappreciated role for RBM12 in the context of the GPCR-cAMP pathway that could be explored further as a tentative molecular mechanism underlying the functions of this factor in neuronal physiology and pathophysiology.

Dynamic Prediction of Outcomes for Youth at Clinical High Risk for Psychosis

Leveraging the dynamic nature of clinical variables in the clinical high risk for psychosis (CHR-P) population has the potential to significantly improve the performance of outcome prediction models. To improve performance of prediction models and elucidate dynamic clinical profiles using joint modeling to predict conversion to psychosis and symptom remission. Data were collected as part of the third wave of the North American Prodrome Longitudinal Study (NAPLS 3), which is a 9-site prospective longitudinal study. Participants were individuals aged 12 to 30 years who met criteria for a psychosis-risk syndrome. Clinical, neurocognitive, and demographic variables were collected at baseline and at multiple follow-up visits, beginning at 2 months and up to 24 months. An initial feature selection process identified longitudinal clinical variables that showed differential change for each outcome group across 2 months. With these variables, a joint modeling framework was used to estimate the likelihood of eventual outcomes. Models were developed and tested in a 10-fold cross-validation framework. Clinical data were collected between February 2015 and November 2018, and data were analyzed from February 2022 to December 2023. Prediction models were built to predict conversion to psychosis and symptom remission. Participants met criteria for conversion if their positive symptoms reached the fully psychotic range and for symptom remission if they were subprodromal on the Scale of Psychosis-Risk Symptoms for a duration of 6 months or more. Of 488 included NAPLS 3 participants, 232 (47.5%) were female, and the mean (SD) age was 18.2 (3.4) years. Joint models achieved a high level of accuracy in predicting conversion (balanced accuracy [BAC], 0.91) and remission (BAC, 0.99) compared with baseline models (conversion: BAC, 0.65; remission: BAC, 0.60). Clinical variables that showed differential change between outcome groups across a 2-month span, including measures of symptom severity and aspects of functioning, were also identified. Further, intra-individual risks for each outcome were more negatively correlated when using joint models (r = -0.92; P < .001) compared with baseline models (r = -0.50; P < .001). In this study, joint models significantly outperformed baseline models in predicting both conversion and remission, demonstrating that monitoring short-term clinical change may help to parse heterogeneous dynamic clinical trajectories in a CHR-P population. These findings could inform additional study of targeted treatment selection and could move the field closer to clinical implementation of prediction models.