N-Acetylcysteine and a Specialized Preventive Intervention for Individuals at High Risk for Psychosis: A Randomized Double-Blind Multicenter Trial.

Background and Hypothesis: Clinical high risk for psychosis (CHR-P) offers a window of opportunity for early intervention and recent trials have shown promising results for the use of N-acetylcysteine (NAC) in schizophrenia. Moreover, integrated preventive psychological intervention (IPPI), applies social-cognitive remediation to aid in preventing the transition to the psychosis of CHR-P patients. Study Design: In this double-blind, randomized, controlled multicenter trial, a 2 × 2 factorial design was applied to investigate the effects of NAC compared to placebo (PLC) and IPPI compared to psychological stress management (PSM). The primary endpoint was the transition to psychosis or deterioration of CHR-P symptoms after 18 months. Study Results: While insufficient recruitment led to early trial termination, a total of 48 participants were included in the study. Patients receiving NAC showed numerically higher estimates of event-free survival probability (IPPI + NAC: 72.7 ±â€…13.4%, PSM + NAC: 72.7 ±â€…13.4%) as compared to patients receiving PLC (IPPI + PLC: 56.1 ±â€…15.3%, PSM + PLC: 39.0 ±â€…17.4%). However, a log-rank chi-square test in Kaplan-Meier analysis revealed no significant difference of survival probability for NAC vs control (point hazard ratio: 0.879, 95% CI 0.281-2.756) or IPPI vs control (point hazard ratio: 0.827, 95% CI 0.295-2.314). The number of adverse events (AE) did not differ significantly between the four groups. Conclusions: The superiority of NAC or IPPI in preventing psychosis in patients with CHR-P compared to controls could not be statistically validated in this trial. However, results indicate a consistent pattern that warrants further testing of NAC as a promising and well-tolerated intervention for CHR patients in future trials with adequate statistical power.

Prevention of First-Episode Psychosis in People at Clinical High Risk: A Randomized Controlled, Multicentre Trial Comparing Cognitive-Behavioral Therapy and Clinical Management Plus Low-Dose Aripiprazole or Placebo (PREVENT).

BACKGROUND: There is limited knowledge of whether cognitive-behavioral therapy (CBT) or second-generation antipsychotics (SGAs) should be recommended as the first-line treatment in individuals at clinical high risk for psychosis (CHRp). HYPOTHESIS: To examine whether individual treatment arms are superior to placebo and whether CBT is non-inferior to SGAs in preventing psychosis over 12 months of treatment. STUDY DESIGN: PREVENT was a blinded, 3-armed, randomized controlled trial comparing CBT to clinical management plus aripiprazole (CM + ARI) or plus placebo (CM + PLC) at 11 CHRp services. The primary outcome was transition to psychosis at 12 months. Analyses were by intention-to-treat. STUDY RESULTS: Two hundred eighty CHRp individuals were randomized: 129 in CBT, 96 in CM + ARI, and 55 in CM + PLC. In week 52, 21 patients in CBT, 19 in CM + ARI, and 7 in CM + PLC had transitioned to psychosis, with no significant differences between treatment arms (P = .342). Psychopathology and psychosocial functioning levels improved in all treatment arms, with no significant differences. CONCLUSIONS: The analysis of the primary outcome transition to psychosis at 12 months and secondary outcomes symptoms and functioning did not demonstrate significant advantages of the active treatments over placebo. The conclusion is that within this trial, neither low-dose aripiprazole nor CBT offered additional benefits over clinical management and placebo.

Bridging the phenomenological gap between predictive basic-symptoms and attenuated positive symptoms: a cross-sectional network analysis.

Attenuated positive symptoms (APS), transient psychotic-like symptoms (brief, limited intermittent psychotic symptoms, BLIPS), and predictive cognitive-perceptive basic-symptoms (BS) criteria can help identify a help-seeking population of young people at clinical high-risk of a first episode psychosis (CHRp). Phenomenological, there are substantial differences between BS and APS or BLIPS. BS do not feature psychotic content as delusion or hallucinations, and reality testing is preserved. One fundamental problem in the psychopathology of CHRp is to understand how the non-psychotic BS are related to APS. To explore the interrelationship of APS and predictive BS, we fitted a network analysis to a dataset of 231 patients at CHRp, aged 24.4 years (SD = 5.3) with 65% male. Particular emphasis was placed on points of interaction (bridge symptoms) between the two criteria sets. The BS 'unstable ideas of reference' and "inability to discriminate between imagination and reality" interacted with attenuated delusional ideation. Perceptual BS were linked to perceptual APS. Albeit central for the network, predictive cognitive basic BS were relatively isolated from APS. Our analysis provides empirical support for existing theoretical accounts that interaction between the distinct phenomenological domains of BS and APS is characterized by impairments in source monitoring and perspective-taking. Identifying bridge symptoms between the symptom domains holds the potential to empirically advance the etiological understanding of psychosis and pave the way for tailored clinical interventions.

(Attenuated) hallucinations join basic symptoms in a transdiagnostic network cluster analysis.

Hallucinations are considered characteristic symptoms of psychosis and part of the 'psychosis superspectrum' of the Hierarchical Taxonomy Of Psychopathology (HiTOP) initiative. To gain insight into their psychopathological relevance, we studied their dimensional placement within a single dense transdiagnostic network constituting of basic symptoms as well as of attenuated and frank psychotic, and related symptoms. Newman's modularity analysis was used to detect symptom clusters in an earlier generated network (Jimeno, N., et al., 2020. Main symptomatic treatment targets in suspected and early psychosis: New insights from network analysis. Schizophr. Bull. 46, 884-895. https://doi.org/10.1093/schbul/sbz140). The constituting 86 symptoms were assessed with the Schizophrenia Proneness Instrument, Adult version (SPI-A), the Structured Interview for Psychosis-Risk Syndromes (SIPS), and the Positive And Negative Syndrome Scale (PANSS) in three adult samples of an early detection service: clinical high-risk (n = 203), first-episode psychosis (n = 153), and major depression (n = 104). Three clusters were detected: "subjective disturbances", "positive symptoms and behaviors", and "negative and anxious-depressive symptoms". The predominately attenuated hallucinations of both SIPS and PANSS joined the basic symptoms in "subjective disturbances", whereas other positive symptoms entered "positive symptoms and behaviors". Our results underline the importance of insight in separating true psychotic hallucinations from other hallucinatory experiences that, albeit phenomenologically similar are still experienced with some insight, i.e., are present in an attenuated form. We conclude that, strictly, hallucinations held with any degree of insight should not be used to diagnose transition to or presence of frank psychoses and, relatedly, to justify antipsychotic medication.

Is there a diagnosis-specific influence of childhood trauma on later educational attainment? A machine learning analysis in a large help-seeking sample.

BACKGROUND: Childhood adversities and trauma (CAT) are associated with poor functional outcome. However, the influence of the single CAT aspects on the risk of a poor functional outcome within different mental disorders has not been investigated so far. Our aims were (i) to predict individual functional outcome based on CAT (ii) to examine whether the prediction power differs within different diagnostic groups (clinical high-risk for psychosis (CHR), psychosis, affective disorders, anxiety disorders) (iii) to compare the specific patterns of CAT experiences, influencing functional outcomes in these groups. METHOD: Clinical data of 707 patients (mean age: 25.09 years (SD = 5.6), 65.5% male) of the Cologne Early Recognition and Intervention Center were assessed with the Trauma And Distress Scale. Functional outcome was estimated by the Social and Occupational Functioning Assessment Scale and school educational attainment. Using machine learning, we generated individualized models to predict functional outcome and to identify specific CAT patterns. RESULTS: Across the entire sample, the best prediction for the functional outcome achieved a balanced accuracy (BAC) of 0.6. After splitting into the single diagnostic groups, an improvement with best results in the psychosis group (BAC = 0.70) was observed. Considering specific CAT patterns, the most predictive items depicted a positive and caring environment - or the absence of these, a positive self-image and experiences of bullying. CONCLUSIONS: Our results indicated that CAT was differentially associated with functional outcome in the various mental disorders. Thus, the importance of mediating variables, that might explain the interindividual differences in the vulnerability to CAT, like resilience factors, appeared to be crucial.

Main Symptomatic Treatment Targets in Suspected and Early Psychosis: New Insights From Network Analysis.

The early detection and intervention in psychoses prior to their first episode are presently based on the symptomatic ultra-high-risk and the basic symptom criteria. Current models of symptom development assume that basic symptoms develop first, followed by attenuated and, finally, frank psychotic symptoms, though interrelations of these symptoms are yet unknown. Therefore, we studied for the first time their interrelations using a network approach in 460 patients of an early detection service (mean age = 26.3 y, SD = 6.4; 65% male; n = 203 clinical high-risk [CHR], n = 153 first-episode psychosis, and n = 104 depression). Basic, attenuated, and frank psychotic symptoms were assessed using the Schizophrenia Proneness Instrument, Adult version (SPI-A), the Structured Interview for Psychosis-Risk Syndromes (SIPS), and the Positive And Negative Syndrome Scale (PANSS). Using the R package qgraph, network analysis of the altogether 86 symptoms revealed a single dense network of highly interrelated symptoms with 5 discernible symptom subgroups. Disorganized communication was the most central symptom, followed by delusions and hallucinations. In line with current models of symptom development, the network was distinguished by symptom severity running from SPI-A via SIPS to PANSS assessments. This suggests that positive symptoms developed from cognitive and perceptual disturbances included basic symptom criteria. Possibly conveying important insight for clinical practice, central symptoms, and symptoms "bridging" the association between symptom subgroups may be regarded as the main treatment targets, in order to prevent symptomatology from spreading or increasing across the whole network.

What happens with schizophrenia patients after their discharge from hospital? Results on outcome and treatment from a "real-world" 2-year follow-up trial.

Aim of the study was to examine the course of schizophrenia patients within 2 years after discharge. Within a multicenter study of the German Competence Network on Schizophrenia, patients suffering from a schizophrenia spectrum disorder were examined regarding their psychopathological improvement, tolerability, and the treatment regime applied during hospitalization and a 2-year follow-up period. Response, remission, the level of everyday functioning, and relapse were furthermore evaluated during the follow-up period using established definitions for these outcome domains. The psychopharmacological treatment was specifically evaluated in terms of a potential association with relapse. 149 patients were available for analysis, with 65% of the patients being in response, 52% in symptomatic remission, and 64% having a satisfiable everyday functioning 2 years after their discharge from hospital. Despite these favorable outcome rates, 63% of the patients suffered from a relapse within the 2-year follow-up period with 86% of these patients being rehospitalized. Discharge non-responder and non-remitter were twice as likely to relapse during follow-up. A significant decrease of side-effects was observed with negligible rates of extrapyramidal side-effects, sedation, and weight gain during follow-up. Patients receiving treatment with atypical antipsychotics were found to have the lowest risk to relapse (p < 0.0001). The results highlight the natural and unsteady course of schizophrenia in most patients underlining the need to develop more specific treatment strategies ensuring ongoing stability and preventing relapse.

Remission in schizophrenia - What are we measuring? Comparing the consensus remission criteria to a CGI-based definition of remission and to remission in major depression.

BACKGROUND: Despite being recommended for use in clinical trials, the consensus remission criteria were found to leave patients with persisting symptoms, relevant areas of functional impairment and a decreased sense of wellbeing. Therefore, to evaluate the appropriateness of the schizophrenia consensus criteria, a definition of remission based on the Clinical Global Impression Scale (CGI) was developed and remitter subgroups were compared. METHODS: 239 patients with a schizophrenia spectrum disorder were evaluated regarding their remission status after inpatient treatment. Remission in schizophrenia was defined according to the symptom-severity component of the consensus criteria by Andreasen et al. and a CGI based definition was calculated using sensitivity and specificity using receiver operating curves (asymptomatic remitter). Both remitter groups (schizophrenia consensus versus asymptomatic remitters) were compared regarding different clinical variables at discharge as well as the likelihood to relapse within a 1-year follow-up period. Both schizophrenia remitter subgroups were compared to remitters in major depression as a reference value. RESULTS: Following the consensus criteria, 63% of the schizophrenia patients were in remission compared to only 18% following the asymptomatic criterion. The schizophrenia consensus remitters were less likely to be concurrent treatment responders (p < 0.0001), had a significantly greater illness severity (p < 0.0001) and less functioning (p = 0.0358) as well as a significantly greater risk to relapse (p = 0.0174) compared to the schizophrenia asymptomatic remitters as well as the depressed remitters. CONCLUSION: It should be critically re-evaluated if the currently proposed consensus criteria are adequate to measure what is traditionally understood to be remission.

Multimodal prevention of first psychotic episode through N-acetyl-l-cysteine and integrated preventive psychological intervention in individuals clinically at high risk for psychosis: Protocol of a randomized, placebo-controlled, parallel-group trial.

AIM: Meta-analyses indicate positive effects of both antipsychotic and cognitive-behavioural interventions in subjects clinically at high risk (CHR) for psychosis in terms of a delay or prevention of psychotic disorders. However, these effects have been limited regarding social functioning and the relative efficacy of both types of interventions remains unclear. Furthermore, neuroprotective substances seem to be a promising alternative agent in psychosis-prevention as they are associated with few and weak side-effects. METHODS: In this multi-centre randomized controlled trial (RCT), we investigate the effects of two interventions on transition to psychosis and social functioning: (a) an integrated preventive psychological intervention (IPPI) including stress-/symptom-management and social-cognitive remediation; (b) N-acetyl-l-cysteine (NAC) as a pharmacological intervention with glutamatergic, neuroprotective and anti-inflammatory capabilities. RESULTS: This is a double-blind, placebo-controlled RCT with regard to NAC and a single-blind RCT with regard to IPPI using a 2 × 2-factorial design to investigate the individual and combined preventive effects of both interventions. To this aim, a total of 200 CHR subjects will be randomized stratified by site to one of four conditions: (a) IPPI and NAC; (b) IPPI and Placebo; (c) NAC and psychological stress management; (d) Placebo and psychological stress management. Interventions are delivered over 26 weeks with a follow-up period of 12 months. CONCLUSION: This paper reports on the rationale and protocol of an indicated prevention trial to detect the most effective and tolerable interventions with regard to transition to psychosis as well as improvements in social functioning, and to evaluate the synergistic effects of these interventions.

Antisaccade and prosaccade eye movements in individuals clinically at risk for psychosis: comparison with first-episode schizophrenia and prediction of conversion.

Saccadic eye movements are well-described markers of cerebral function and have been widely studied in schizophrenia spectrum populations. However, less is known about saccades in individuals clinically at risk for schizophrenia. Therefore, we studied individuals in an at-risk mental state (ARMS) (N = 160), patients in their first episode of schizophrenia (N = 32) and healthy controls (N = 75). N = 88 ARMS participants showed an early at-risk mental state (E-ARMS), defined by cognitive-perceptive basic symptoms (COPER) or a combination of risk and loss of function, whereas N = 72 were in a late at-risk mental state (L-ARMS), defined by attenuated psychotic symptoms or brief limited intermittent psychotic symptoms. We examined prosaccades, reflecting overt attentional shifts, and antisaccades, measuring inhibitory control, as well as their relationship as an indicator of the interplay of bottom-up and top-down influences. L-ARMS but not E-ARMS participants had increased antisaccade latencies compared to controls. First-episode patients had higher antisaccade error rates compared to E-ARMS participants and controls, and increased latencies compared to all other groups. Prosaccade latencies did not differ between groups. We observed the expected negative correlation between prosaccade latency and antisaccade error rate, indicating that individuals with shorter prosaccade latencies made more antisaccade errors. The magnitude of the association did not differ between groups. No saccadic measure predicted conversion to psychosis within 2 years. These findings confirm the existence of antisaccade impairments in patients with schizophrenia and provide evidence that volitional response generation in the antisaccade task may be affected even before onset of clinically overt psychosis.

The interrelationship between schizotypy, clinical high risk for psychosis and related symptoms: Cognitive disturbances matter.

Schizotypy and clinical high risk (CHR) criteria can identify individuals who are at increased risk for developing psychosis in community and patient samples. However, both approaches have rarely been combined, and very little is known about their associations. Therefore, we examined the factorial structure of CHR and related symptoms and schizotypy features as well as their interrelationship for the first time in a comprehensive approach. In a sample of 277 patients (22 ±â€¯6 years) from two early detection services, structural equation modeling including confirmatory factor analysis was performed to test a theory-driven model using four Wisconsin Schizotypy Scales, 14 predictive basic symptoms (BS) of the Schizophrenia Proneness Instrument, and positive, negative, and disorganized symptoms from the Structured Interview for Psychosis-Risk Syndromes. The data fitted well to the six hypothesized latent factors consisting of negative schizotypy, positive schizotypy including perceptual BS, negative symptoms, positive symptoms, disorganized symptoms and cognitive disturbances. As postulated, schizotypy features were significantly associated with positive, negative and disorganized symptoms through cognitive disturbances. Additionally, positive and negative schizotypy also had a direct association with the respective symptom-domain. While the identified factorial structure corresponds well to dimensional models of schizotypy and psychoses, our model extends earlier models by indicating that schizotypy features are associated with positive, negative and disorganized symptoms directly or indirectly via subjective cognitive disturbances. This calls for more attention to subjective cognitive deficits in combination with heightened schizotypy in the early detection and intervention of psychoses - or even of an Attenuated Psychosis Syndrome.

Predictors of treatment response to psychological interventions in people at clinical high risk of first-episode psychosis.

AIM: Psychological interventions, such as cognitive behavioural therapy (CBT) and supportive counselling (SC), are used to treat people with schizophrenia and people at clinical high risk (CHR) of psychosis. However, little information is available on predictors of treatment response. This study aims to identify such predictors of psychological interventions in CHR. METHODS: A total of 128 help-seeking CHR outpatients were randomized into two groups-integrated psychological intervention (IPI), including CBT, and SC-for 12 months. Multiple regression analysis was used to identify demographic, symptomatic and functional variables that predict improvement in positive (PANSS Positive), negative (PANSS Negative) and basic symptoms (Basic symptom total score) and improvement in functioning (GAF) at 1-year follow up. RESULTS: In the merged group (IPI + SC), people who lived independently, were younger and presented with higher baseline functioning showed more improvement in symptomatic outcomes at follow up. Negative symptoms at baseline predicted less improvement in positive and basic symptoms. Being married or cohabiting and living in the primary family were found to correlate with good functioning at 1-year follow up. CONCLUSIONS: Younger CHR individuals and those who are functioning well may particularly benefit from early intervention. Treatment might need to be modified for low-functioning CHR and those who already display higher scores of negative symptoms. Registration number: NCT00204087.