Auswahl der wissenschaftlichen Literatur zum Thema „Clinical High-Risk State for Psychosis (CHR-P)“

IntroductionSpeaking prospectively we use the concept of “at risk mental state” (ARMS) to describe the state in which a person has a heightened risk of developing a psychotic disorder. Young people who are experiencing ARMS can be more precisely defined as being at ultra-high-risk of psychosis using a specific set of criteria known as the UHR criteria.ObjectivesTo clarify the concept of ultra-high-risk individuals and to characterize the clinical and functional characteristics and general psychopathology of those individuals that do not transition to psychosis during the follow-up period.MethodsResearch on UpToDate using the terms “Ultra-High-Risk”; “psychosis”, “transition”.ResultsRecent literature has suggested that less than 30% of those who meet established criteria for being at Clinical-High-Risk of psychosis (CHR-P) go on to develop a psychotic illness. It is therefore of crucial importance and relevance to assess and clarify what happens to high-risk individuals who do not transition to psychosis, who make up the vast majority.One of the most recent studies (NAPLS-2) that encompassed 764 of CHR-P individuals who were followed for 2 years, concluded that 278 did not transition to psychosis during the follow-up period. Three clinical outcomes were recorded: 1 group had experienced a psychopathological remission (39.57%); the other kept symptomatic but not currently meeting criteria for a prodromal risk syndrome (33.45%); the third group had a prodromal progression (26.98%). The study concluded among others that although the remission group had improved social functioning at 2 years compared with the other groups, they were still functioning below the healthy control group.Another meta-analysis that included a total of 2756 CHR-P individuals with a mean duration of follow-up of 30.7 months evaluated several clinical outcomes in CHR-P that didn’t transitioned to psychosis and between CHR-P non-transitioning versus those transitioning to psychosis. It concluded that CHR-P that do not transition to psychosis have an overall improvement of symptoms (APS, negative, depressive) and functioning at follow-up compared to baseline.ConclusionsThe occurrence of a first psychotic episode is often devastating for the patient and their family, especially given its usual onset in adolescence and early adulthood. This is a critical period in the individual’s development as a person, and disorders at this stage can threaten the potential for a productive and inclusive adult life. Studies have suggested that less than 30% of individuals classified as UHR actually develop a psychotic disorder.However, little is known about the individuals belonging to this group who do not transition to psychosis. We therefore consider it is relevant to clarify the clinical and functional outcomes of this group of individuals.Disclosure of InterestNone Declared

Abstract Background Genetic vulnerability to psychosis is polygenic, involving multiple genes with small individual effects (Psychiatric Genomics Consortium (PGC), 2014). The risk of psychosis is also related to environmental factors, such as childhood trauma (Lardinois et al, 2011). Although the onset of psychosis is thought to result from the interaction of genetic and environmental risk factors (Walker & Diforio, 1997), the extent to which the influence of childhood trauma depends on genetic susceptibility remains unclear. We sought to address this issue in a large prospective study of people at clinical high risk (CHR) for psychosis. These individuals present with psychotic and affective symptoms, and are at increased risk of developing both schizophreniform and affective psychoses. Methods We studied subjects of European ancestry, drawn from EU-GEI, a large multi-centre prospective study of people at CHR for psychosis. At baseline, DNA was obtained from subjects who met the CAARMS criteria for the CHR state (n=266) and healthy controls (HC; n=42). Childhood trauma was assessed using the childhood trauma questionnaire (CTQ), which comprises 5 subdomains: emotional abuse, physical abuse, sexual abuse, physical neglect, and emotional neglect. Polygenic risk scores (PRSs) for schizophrenia (SCZ), bipolar disorder (BD) and major depressive disorder (MDD) were constructed separately, using results from meta-analyses by the corresponding Disorder Working Groups of the PGC. The CHR subjects were clinically monitored for up to 5 years and clinical outcomes were assessed in terms of transition to psychosis (as defined by the CAARMS), remission from the CHR state (subject no longer meets CAARMS inclusion criteria) and level of functioning (GAF Disability Scale). Logistic regression models were used to investigate the association between each PRSs and childhood trauma as predictors of transition and remission, adjusted by population stratification using the first 10 principal components, age, sex and site. All findings are reported at p<0.017, Bonferroni-corrected for the 3 PRSs. Results Within the CHR sample, the onset of psychosis during follow up was related to interactions between the BD PRS and the total childhood trauma score (OR=0.959, 95% CI 0.930–0.988, p=0.006), and between the BD PRS and physical abuse (OR=0.787, 95% CI 0.689–0.900, p<0.001). Remission from the CHR state was related to an interaction between the SCZ PRS and childhood sexual abuse (OR: 1.110, 95% CI 1.004–1.226, p=0.041). Discussion These data indicate that clinical outcomes in CHR subjects are related to interactions between the polygenic risk for psychotic disorders and childhood adversity. The measurement of interactions between genomic and environmental risk factors may help to predict individual outcomes in people at high risk in a clinical setting.

Introduction Early detection of psychosis is a promising area in preventive psychiatry. The use of early intervention can prevent the first episode psychosis and improve outcomes. Objectives Identification of premorbid features of depressive patients at clinical high risk for psychosis (CHR) comparing with depressive patients without CHR in order to improve early recognition of the psychotic process. Methods 219 young depressive in-patients with CHR criteria for SOPS with attenuated positive and attenuated negative symptoms and 52 young depressive in-patients without CHR were examined. Presence of obstetric complications, neurodevelopmental deviance, neurological and psychiatric signs at the premorbid stage, and the level of premorbid functioning on the PAS were examined. Results It has been established that depressive patients at CHR and without CHR had some obstetric complications (57.5% and 40.4%, respectively). Neurodevelopmental deviance in the first year of live was in 57.5% patients with CHR. At the age of 3-5 sleep disorders, ADHD and phobias were more common in patients at CHR than without it (58.8% and 32.7%, p=0.014). In pubertal, patients at CHR were more likely to show depression symptoms, obsessions, and aggression - 90.4% versus 76.9% (p=0.029). On the PAS scale, a decrease of the level of premorbid functioning has been observed in two groups of patients with and without CHR from the age of 12: from 12 to 15 years, 0.4 and 0.3 (p=0.004), from 16 to 18 years, 0.47 and 0.37 (p 0.001). Conclusions Premorbid functioning were worst in patients with CHR, which indicates the possibility of early clinical detection of psychosis. Disclosure No significant relationships.

Abstract Background The Clinical High Risk state (CHR) concept was implemented to promote the early detection of young help-seeking patients with higher risk of psychotic transition. This category is based on specific clinical criteria (EPA, 2015) and require narrow frequency/duration ratings of subclinical positive psychotic symptoms to allow its definition. Prevalence of CHR “category” appears nevertheless rare in help-seeking young people and the rate of psychotic transition of CHR state is lower than predicted by early studies. Therefore, the binary outcome of transition to psychosis proposed by the “CHR model” actually fails to be an efficient marker to stratify, in neurobiological studies, people with different psychopathological trajectories, notably those who develop psychosis from those who do not. In order to rely on a vulnerability model for schizophrenic psychosis more sensitive to psychosocial functioning and negative dimension, we study prospectively with three years of follow-up a population of help-seekers addressed for clinical suspicion of prodromal state of psychosis. We aimed here to identify subgroups of patients in a sample of subclinical psychotic states using psychological and cognitive outcomes as profiling criteria, focusing not only on transition but also on psychosocial functioning as main outcome. Methods A total of 32 help-seeking adolescents and young adults aged 14 to 35 were referred by health care providers for a specialized evaluation in case of suspicion of a prodromal psychotic state and/or detected by the French version of the Prodromal Questionnaire (PQ-16; cut-off 6/16). Their CHR status was assessed by the Structured Interview for Psychosis-Risk Syndromes (SIPS) and the Schizophrenia Proneness Instrument, Adult (SPI-A). Individuals included in the study presented either a CHR status, a subclinical CHR status or negative symptomatology. All subjects performed an additional neuropsychological battery and blood test for redox markers (Glutathione Peroxidase (GPx) and Glutathione Reductase (GR) activities) (Xin et al, 2016). Based on their clinical profile, we made a stratification of the patients using a Principal Component Analysis. Results Cognitive and psychological outcome stratification of all help-seekers revealed two subgroups (called group1 and group2) of patients with distinct profiles. Individuals in group1 (n=18) had greater levels of basic symptoms and general symptomatology. On the other hand, in group2 (n=14), individuals showed a weaker self-esteem and a lower rate of “living independently”. Cognitive scores for speed processing, attention, verbal learning and social cognition were significantly lower in group2 compared to group1. In addition, these cognitive outcomes were negatively correlated with negative symptoms only in group2. Analysis of redox markers revealed a positive correlation between GPx and GR activities in group1, a correlation disrupted in group2. Discussion Stratification of a cohort of young help-seekers with suspicion of prodromal psychosis, regardless of their CHR status, allowed us to distinguish two subgroups with different clinical profiles: group1 with higher levels of basic symptoms and general symptomatology, and group2 with weaker self-esteem, less autonomy and poorer neurocognition. In addition, analysis of redox markers revealed a redox dysregulation in patients with poorer cognitive profile. Considering the impact of neurocognitive impairment on functioning, special focus to patients of group2 is needed, mostly in clinical practice. Moreover, they might benefit of supplementation with antioxidant compounds such as NAC, which may improve cognitive deficits (Conus et al, 2018).

The aim of the review: the analysis of modern Russian and foreign literature dedicated to the problem of determining diagnostic criteria for clinical high risk of psychosis (CHR-P) and outlining the therapeutic approaches based on the pathogenic mechanisms of their development. Material and method: the publications found by searching queries for keywords in Russian and English in the MEDLINE/PubMed and eLIBRARY databases for the time period from 2010 to 2020 were then analyzed. Conclusion: the review presents a modern definition of the CHR-P group, along with a clarification of individual diagnostic criteria, which include attenuated psychotic symptoms (APS), brief limited intermittent psychotic symptoms (BLIPS), genetic risk with deterioration of premorbid functioning, as well as basic symptoms (BS). We found heterogeneity of the CHR-P group with different levels of manifestation and outcomes and indicated the involvement of different pathogenic mechanisms in their formation. These findings determine the development of various approaches to treatment, which involve the assessment of the ratio of potential benefits and the risks of side effects. The obtained data, on the one hand, attest to the prospective viability of the therapeutic approach to the patients with CHR-P with the possibility of influencing the course of the disease, delaying its manifestation and improving long-term outcomes, and, on the other hand, the lack of universal standards of therapy at present. Tactics of treatment are determined basing on an individual approach to the patient with a comprehensive psychopathological assessment of complaints, clinical state and its dynamics.

There is emerging evidence that identification and treatment of individuals in the prodromal or clinical high-risk (CHR) state for psychosis can reduce the probability that they will develop a psychotic disorder. Event-related brain potentials (ERPs) are a noninvasive neurophysiological technique that holds promise for improving our understanding of neurocognitive processes underlying the CHR state. We aimed to systematically review the current literature on cognitive ERP studies of the CHR population, in order to summarize and synthesize the results, and their implications for our understanding of the CHR state. Across studies, amplitudes of the auditory P300 and duration mismatch negativity (MMN) ERPs appear reliably reduced in CHR individuals, suggesting that underlying impairments in detecting changes in auditory stimuli are a sensitive early marker of the psychotic disease process. There are more limited data indicating that an earlier-latency auditory ERP response, the N100, is also reduced in amplitude, and in the degree to which it is modulated by stimulus characteristics, in the CHR population. There is also evidence that a number of auditory ERP measures (including P300, MMN and N100 amplitudes, and N100 gating in response to repeated stimuli) can further refine our ability to detect which CHR individuals are most at risk for developing psychosis. Thus, further research is warranted to optimize the predictive power of algorithms incorporating these measures, which could help efforts to target psychosis prevention interventions toward those most in need.

Between 2012-2017, 300 individuals completed the baseline assessment, 205 of them met criteria for CHR-P or First-Episode Psychosis, and 154 accepted the enrolment in the ReARMS for treatment and follow-up. Empirical contributions based on the ReARMS dataset involved the structure of assessment and intervention, the Italian validation of ad-hoc instruments of assessment, clinical features of enrolled individuals (anhedonia, aberrant salience, suicidality and metacognition) and longitudinal trajectories in terms of outcome and response to treatments. age between adolescence and young adulthood, being effective in intercepting an early and usually enduring psychopathological suffering, independently from the transition to psychosis. Rather than being rigidly focused on homotypic trajectories from CHR-P to psychosis, increasing evidence on heterotypic trajectories starting from CHR-P to multiple psychopathological outcomes suggest to update early intervention services toward increased organizational flexibility, for example in therapeutic options.

Abstract Background Primary prevention in Clinical High Risk for psychosis (CHR-P) can ameliorate the course of psychotic disorders. Further advancements of knowledge have been slowed by the standstill of the field, which is mostly attributed to its epidemiological weakness. This underlies the limited identification power for at-risk individuals and the relatively modest ability of CHR-P interviews to rule-in a state of risk for psychosis. One potential avenue for improving identification of individuals at risk for psychosis is a Psychosis Polyrisk Score (PPS) integrating genetic and non-genetic risk and protective factors for psychosis. The PPS hinges on recent findings that risk enrichment in CHR-P samples is accounted for by the accumulation of non-genetic factors e.g. parental and sociodemographic risk factors, perinatal risk factors, later risk factors, and antecedents. Methods A prototype of the PPS has been developed encompassing 26 non-genetic risk and protective factors, utilising Relative Risks (RR) from an umbrella review of risk and protective factors for psychosis onset in the general population. This was combined with prevalence data to ensure positive scores indicated increased psychosis risk and negative scores indicated decreased psychosis risk. To pilot this, patients referred for a CHR-P assessment (n=15) and healthy controls (n=66) were recruited and assessed with the PPS. Additionally, to investigate the range and distribution of these scores in the general population, 10,000,000 permutations were run utilising prevalence data to produce a simulated dataset. Results In the simulated general population data, scores ranged from -15 (least risk, equivalent RR = 0.03) to 39.5 (highest risk, RR = 8912.51). 50% of individuals had an RR < 1 (PPS < 0), 26.7% of individuals had an RR > 3 (PPS > 5), and 2.7% RR > 30 (PPS > 15). Patients referred for a CHR-P assessment had higher PPS scores (median=9, IQR=12.75) than healthy controls (median=-1.75, IQR=8.875). PPS scores in the simulated general population dataset (median=0, IQR=9.5) were similarly lower than patients. Discussion The PPS has potential for improving identification of individuals at risk for psychosis. Its distribution in a simulated general population is reflective of expected psychosis risk, with the vast majority of people not being at-risk and very few being at high risk. In addition to supplementing current assessments for CHR-P, this could be implemented at an earlier stage to stratify individuals based on psychosis risk and inform prognoses and clinical decision-making. This promise warrants further research to ascertain its prognostic accuracy and optimal thresholds for clinical intervention.

ObjectiveClinical high risk (CHR) for psychosis state is characterized by presence of potentially prodromal for schizophrenia symptoms. The aim of this study was to assess the predictors of transition to first psychotic episode.MethodsThe study included 123 CHR subjects. All the subjects were characterized by the presence of one of the group of criteria: (1) UHR criteria, (2) basic symptoms criteria and (3) negative symptoms and formal thought disorders (FTD). The presence of FTD in clinical high-risk individuals was assessed with methods of experimental pathopsychology. The mean length of follow-up was 26 months (SD 18). All subjects were males, mean age = 20.2 (SD: 2.1). We examined the subjects’ performance using the Cambridge automated neuropsychological test battery. We applied survival analyses to determine associations between a transition to psychosis and sociodemographic, clinical and neurocognitive parameters. To determine which items are the best predictors, Cox regression analyses were applied.ResultsThe psychosis developed in 39 subjects (31.7%). Global assessment of functioning, positive symptoms, blunted affect, social isolation, impaired role function, disorganizing/stigmatizing behavior, basic symptoms (thought pressure, unstable ideas of reference), neurocognitive parameters (visual memory and new learning, decision making, executive function) significantly influenced the transition to psychosis. A prediction model was developed and included unusual thought content (Wald = 12.386, P < 0.0001, HR = 2.996), perceptual abnormalities (Wald = 4.777, P = 0.029, HR = 1.43) and impaired role function (Wald = 1.425, P < 0.028, HR = 4.157).ConclusionClinical measures are important predictors for transition to psychosis in high-risk individuals.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Les troubles psychotiques sont caractérisés par d’importantes conséquences fonctionnelles avec des preuves émergentes concernant l’altération des fonctions visuelles de bas niveau. Le lien anatomique et fonctionnel entre la rétine et le cortex visuel a notamment permis d’émettre des hypothèses quant à l’association entre les altérations des deux étages visuels. Nous avons investigué les mesures électrophysiologiques visuelles rétiniennes et corticales dans les troubles du spectre de la schizophrénie et dans les situations à risque de psychose dont l’usage régulier de cannabis et les phases précoces de psychose font partie intégrante. Les résultats ont mentionné des altérations portant sur la plupart des cellules rétiniennes et des déficits au regard du cortex visuel primaire, avec un lien potentiel entre les deux types de mesures dans la schizophrénie. L’intérêt des biomarqueurs électrophysiologiques réside également dans le lien décrit avec les symptômes de la psychose, ce qui incite ainsi à les utiliser davantage en pratique clinique à des fins d’améliorations diagnostiques
Psychotic disorders are characterized by severe functional consequences, with emerging evidence of impairment in low-level visual functions. Most notably, the anatomical and functional link between the retina and the visual cortex led to hypotheses concerning the association between alterations in both visual stages. We investigated retinal and cortical visual electrophysiological measurements in schizophrenia spectrum disorders and situations at risk of psychosis, of which regular cannabis use and early phases of psychosis are an integral part. The results highlighted alterations in most retinal cells and deficits in the primary visual cortex, with a potential link between both measures in schizophrenia. The relevance of electrophysiological biomarkers also lies in the link described with psychotic symptoms, motivating them to be used more widely in clinical practice to improve diagnosis

This chapter considers treatment approaches in early psychosis and the possibility of prevention prior to the development of illness. The chapter first considers the various definitions of the pre-psychotic state, including prodrome, and the concept of clinical high-risk (CHR) groups. The CHR groups, including the ultra-high-risk (UHR) and basic symptoms (BS) groups aim to identify individuals at imminent risk of transitioning to full-blown psychosis. Further, the chapter summarizes the notion of a staging model for psychosis, which incorporates these earliest pre-psychosis stages, and considers the onset and progression of the illness to chronicity, with differing intervention options for each stage. The relevance of interventions targeting non-specific risk factors, such as trauma, stress, bullying, drug abuse, and migration, in the early years is considered. The chapter discusses possible interventions to prevent or delay psychosis onset or progression (for example, prenatal choline or vitamin D), and public health measures at the population level. It also explores the issues relating to drug prescribing in the pre-psychosis stage and outlines controversies regarding the risk–benefit ratio and ethics of these pre-emptive strategies. Models of care aimed to reduce the duration of untreated psychosis may prove useful. Integrative treatment in early psychosis has been more successful than ‘treatment as usual’ in reducing symptoms, relapse rates, and improving engagement. Early detection and intervention services and public awareness campaigns are key to primary prevention. Studies that investigate trajectories of symptom development and emergence of psychosis are needed, in order to evaluate the effectiveness of pre-emptive and later interventions.

In 2006, investigators compiled data from the public mental health systems of eight states in the USA and compared life expectancy for patients with a major mental illness with general population values. Focusing on states with outpatient as well as inpatient data, this study indicated that individuals with a major mental illness have a mean age at death that is 25–30 years earlier than that observed in the general population over the same years in the same states (1). In this study, ‘major mental illness’ included affective disorders such as major depression and bipolar disorder, attention deficit/hyperactivity disorders, schizophrenia, and schizoaffective disorders. Importantly, these data indicated that the leading cause of death in the mentally ill is coronary heart disease (CHD) and when death due to stroke or cerebrovascular disease is included in a category of cardiovascular disease (CVD), they account for more than 35% of deaths in this population. Suicide, by contrast, was responsible for fewer than 5% of deaths overall. Such observations have led to growing clinical interest in the cardiovascular and metabolic risk factors that contribute to the major causes of morbidity and mortality in patients with psychotic disease, as exemplified by schizophrenia.