Publications by authors named "Mark van der Gaag"

158 Publications

Differential trajectories of tobacco smoking in people at ultra-high risk for psychosis: Associations with clinical outcomes.

Front Psychiatry 2022 22;13:869023. Epub 2022 Jul 22.

Department of Psychiatry, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.

Objective: People at ultra-high risk (UHR) for psychosis have a high prevalence of tobacco smoking, and rates are even higher among the subgroup that later develop a psychotic disorder. However, the longitudinal relationship between the course of tobacco smoking and clinical outcomes in UHR subjects is unknown.

Methods: We investigated associations between tobacco smoking and clinical outcomes in a prospective study of UHR individuals ( = 324). Latent class mixed model analyses were used to identify trajectories of smoking severity. Mixed effects models were applied to investigate associations between smoking trajectory class and the course of attenuated psychotic symptoms (APS) and affective symptoms, as assessed using the CAARMS.

Results: We identified four different classes of smoking trajectory: (i) Persistently High ( = 110), (ii) Decreasing ( = 29), (iii) Persistently Low ( = 165) and (iv) Increasing ( = 20). At two-year follow-up, there had been a greater increase in APS in the Persistently High class than for both the Persistently Low (ES = 9.77, SE = 4.87, = 0.046) and Decreasing (ES = 18.18, SE = 7.61, = 0.018) classes. There were no differences between smoking classes in the incidence of psychosis. There was a greater reduction in the severity of emotional disturbance and general symptoms in the Decreasing class than in the High (ES = -10.40, SE = 3.41, = 0.003; ES = -22.36, SE = 10.07, = 0.027), Increasing (ES = -11.35, SE = 4.55, = 0.014; ES = -25.58, SE = 13.17, = 0.050) and Low (ES = -11.38, SE = 3.29, = 0.001; ES = -27.55, SE = 9.78, = 0.005) classes, respectively.

Conclusions: These findings suggests that in UHR subjects persistent tobacco smoking is associated with an unfavorable course of psychotic symptoms, whereas decrease in the number of cigarettes smoked is associated with improvement in affective symptoms. Future research into smoking cessation interventions in the early stages of psychoses is required to shine light on the potential of modifying smoking behavior and its relation to clinical outcomes.
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http://dx.doi.org/10.3389/fpsyt.2022.869023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9356251PMC
July 2022

The Relationship Between Grey Matter Volume and Clinical and Functional Outcomes in People at Clinical High Risk for Psychosis.

Schizophr Bull Open 2022 Jan 20;3(1):sgac040. Epub 2022 Jun 20.

Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, UK.

Objective: To examine the association between baseline alterations in grey matter volume (GMV) and clinical and functional outcomes in people at clinical high risk (CHR) for psychosis.

Methods: 265 CHR individuals and 92 healthy controls were recruited as part of a prospective multi-center study. After a baseline assessment using magnetic resonance imaging (MRI), participants were followed for at least two years to determine clinical and functional outcomes, including transition to psychosis (according to the Comprehensive Assessment of an At Risk Mental State, CAARMS), level of functioning (according to the Global Assessment of Functioning), and symptomatic remission (according to the CAARMS). GMV was measured in selected cortical and subcortical regions of interest (ROI) based on previous studies (ie orbitofrontal gyrus, cingulate gyrus, gyrus rectus, inferior temporal gyrus, parahippocampal gyrus, striatum, and hippocampus). Using voxel-based morphometry, we analysed the relationship between GMV and clinical and functional outcomes.

Results: Within the CHR sample, a poor functional outcome (GAF < 65) was associated with relatively lower GMV in the right striatum at baseline ( < .047 after Family Wise Error correction). There were no significant associations between baseline GMV and either subsequent remission or transition to psychosis.

Conclusions: In CHR individuals, lower striatal GMV was associated with a poor level of overall functioning at follow-up. This finding was not related to effects of antipsychotic or antidepressant medication. The failure to replicate previous associations between GMV and later psychosis onset, despite studying a relatively large sample, is consistent with the findings of recent large-scale multi-center studies.
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http://dx.doi.org/10.1093/schizbullopen/sgac040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9309497PMC
January 2022

Improving screening methods for psychosis in an adolescent help-seeking population using the Child Behavior Checklist (CBCL) and the Youth Self Report (YSR) versus the Prodromal Questionnaire -16 items version (PQ-16).

Child Adolesc Psychiatry Ment Health 2022 Mar 31;16(1):25. Epub 2022 Mar 31.

Parnassia Psychiatric Institute, Rotterdam and The Hague, the Netherlands.

Background: Screening methods for detecting Ultra High Risk status (UHR) or psychosis should be improved, especially in adolescent samples. We therefore tested whether the Child Behavior Checklist (CBCL) and the Youth Self Report (YSR) add value to the Prodromal Questionnaire-16 items version (PQ-16) for detecting UHR status or psychosis.

Methods: We included help-seeking adolescents who had completed the PQ-16, YSR, CBCL, and a Comprehensive Assessment of an At Risk Mental States (CAARMS) interview, and used independent samples t-tests and binary logistic regression analyses to determine the scales contributing to the prediction of UHR status or of having reached the psychosis threshold (PT). Cutoff scores were determined using ROC analyses.

Results: Our sample comprised 270 help-seeking adolescents (mean age 14.67; SD 1.56, range 12-17); 67.8% were girls and 66.3% were of Dutch origin. The Thought Problems syndrome scales of both the YSR and the CBCL best predicted UHR or PT, and had screening values comparable to the PQ-16. Other syndrome scales did not improve screening values. Although combining measures reduced the number of false negatives, it also increased the number of adolescents to be interviewed. The best choice was to combine the YSR Thought Problems scale and the PQ-16 as a first-step screener.

Conclusions: Combining measures improves the detection of UHR or PT in help-seeking adolescents. The Thought Problems subscales of the YSR and CBCL can both be used as a first-step screener in the detection of UHR and/or psychosis. Trial registration Permission was asked according to the rules of the Ethics Committee at Leiden. This study is registered as NL.44180.058.13.
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http://dx.doi.org/10.1186/s13034-022-00459-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8973987PMC
March 2022

Efficacy of Acceptance and Commitment Therapy in Daily Life in Early Psychosis: Results from the Multi-Center INTERACT Randomized Controlled Trial.

Psychother Psychosom 2022 Mar 18:1-13. Epub 2022 Mar 18.

Department of Public Mental Health, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.

Introduction/objective: This study aimed to investigate efficacy of Acceptance and Commitment Therapy in Daily Life (ACT-DL), combining face-to-face therapy with an Ecological Momentary Intervention (EMI), in addition to treatment as usual (TAU) for psychotic distress, in comparison to TAU.

Methods: Individuals aged 15-65 years with clinically established ultra-high risk or first episode of psychosis were randomly assigned to TAU or ACT-DL+TAU. ACT-DL+TAU consisted of 8 ACT-sessions augmented with an EMI-app. The primary outcome was psychotic distress assessed with the Comprehensive Assessment scale of At Risk Mental State (CAARMS) at post-intervention and 6- and 12-month follow-up. Secondary outcomes were functioning, symptom severity, and momentary psychotic distress. We performed multivariate mixed models according to intent-to-treat principles.

Results: Between June 1, 2015 and December 31, 2018, 668 participants were referred, of whom 148 were randomized to ACT-DL+TAU (n = 71) or TAU (n = 77). One hundred and fifteen (78%) provided primary outcome data at least at one follow-up assessment. There was no evidence of greater reduction in the primary outcome measure CAARMS distress in ACT-DL+TAU compared to TAU (χ2(3) = 2.36; p = 0.50). However, out of the tested secondary outcomes, global functioning (χ2(3) = 9.05; p = 0.033), and negative symptoms (χ2(3) = 19.91; p<0.001) improved in ACT-DL+TAU compared to TAU, as did momentary psychotic distress (χ2(3) = 21.56; p < 0.001).

Conclusions: INTERACT did not support a significant effect of ACT-DL over TAU on the primary outcome measure of psychotic distress as assessed with the CAARMS. Although significant improvements were found for some secondary outcome measures, further replication studies are needed to confirm the strength and specificity of these effects.
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http://dx.doi.org/10.1159/000522274DOI Listing
March 2022

Verbal memory performance predicts remission and functional outcome in people at clinical high-risk for psychosis.

Schizophr Res Cogn 2022 Jun 28;28:100222. Epub 2021 Oct 28.

Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, United Kingdom.

Robust deficits in cognitive functioning are present in people with psychosis and are evident in the early stages of the disorder. Impairments in verbal memory and verbal fluency are reliably seen in individuals at clinical high-risk for psychosis (CHR) compared to healthy populations. As previous studies have shown a relationship between cognition and longer-term outcomes in schizophrenia, the aim of this paper was to explore whether verbal memory and verbal fluency performance predicted outcomes in a large CHR sample recruited as part of the EU-GEI High Risk Study. Participants included 316 CHR individuals, 90.8% of whom were not currently on antipsychotic medication, and 60 healthy controls. Verbal memory and verbal fluency performance were measured at baseline. At two-year follow-up, CHR individuals were assessed by three different outcome measures, those who did and did not (1) transition to psychosis, (2) experience burdening impairment or disabilities, or (3) remit clinically from CHR status. Individuals with CHR displayed significant verbal memory and verbal fluency deficits at baseline compared to healthy controls (Hedges' effect size = 0.24 to 0.66). There were no significant differences in cognitive performance of those who did and did not transition to psychosis. However, impaired immediate verbal recall predicted both functional disability and non-remission from the CHR state. Results remained significant when analyses were restricted to only include antipsychotic-free CHR participants. These findings may inform the development of early interventions designed to improve cognitive deficits in the early stages of psychosis.
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http://dx.doi.org/10.1016/j.scog.2021.100222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8861401PMC
June 2022

Clinical, societal and personal recovery in schizophrenia spectrum disorders across time: states and annual transitions.

Br J Psychiatry 2021 07;219(1):401-408

Rob Giel Research Center, University Center for Psychiatry, University Medical Center Groningen, University of Groningen, The Netherlands.

Background: Recovery in schizophrenia is a complex process, involving clinical, societal and personal recovery. Until now, studies analysed these domains separately, without examining their mutual relations and changes over time.

Aims: This study aimed to examine different states of recovery and transition rates between states.

Method: The Pharmacotherapy Monitoring and Outcome Survey (2006-2017) yearly assesses patients with schizophrenia in the Northern Netherlands. Data from 2327 patients with one up to 11 yearly measurements on clinical, societal and personal recovery were jointly analysed with a mixture latent Markov model (MLMM).

Results: The selected MLMM had four states that differed in degree and pattern of recovery outcomes. Patients in state 1 were least recovered on any domain (16% of measurements), and partly recovered in states 2 (25%; featured by negative symptoms) and 3 (21%; featured by positive symptoms). Patients in state 4 (38%) were most recovered, except for work, study and housekeeping. At the subsequent measurement, the probability of remaining in the same state was 77-89%, transitioning to a better state was 4-12% and transitioning to a worse state was 4-6%; no transitions occurred between states 1 and 4. Female gender, shorter illness duration and less schizophrenia were more prevalent in better states.

Conclusions: Quite a high recovery rate was present among a substantial part of the measurements (38%, state 4), with a high probability (89%) of remaining in this state. Transition rates in the other states might increase to a more favourable state by focusing on adequate treatment of negative and positive symptoms and societal problems.
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http://dx.doi.org/10.1192/bjp.2021.48DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8529640PMC
July 2021

Voice phenomenology as a mirror of the past.

Psychol Med 2022 Jan 7:1-9. Epub 2022 Jan 7.

Department of Psychology, Institute of Psychiatry, Psychology & Neuroscience, King's College London, De Crespigny Park, LondonSE5 8AF, UK.

Background: Post-traumatic mechanisms are theorised to contribute to voice-hearing in people with psychosis and a history of trauma. Phenomenological links between trauma and voices support this hypothesis, as they suggest post-traumatic processes contribute to the content of, and relationships with, voices. However, research has included small samples and lacked theory-based comprehensive assessments.

Method: In people with distressing voices (n = 73) who experienced trauma prior to voice-hearing, trauma-voice links were assessed both independently and dependently (descriptions were presented and rated separately and together, respectively) by both participants and researchers. A structured coding frame assessed four types of independent links (i.e. victimisation type, physiological-behavioural, emotional, and cognitive response themes including negative self-beliefs) and three types of dependent links: relational (similar interaction with/response to, voice and trauma); content (voice and trauma content are exactly the same); and identity (voice identity is the same as perpetrator).

Results: Independent links were prevalent in participants (51-58%) and low to moderately present in researcher ratings (8-41%) for significant themes. Identification of negative self-beliefs in trauma was associated with a significantly higher likelihood of negative self-beliefs in voices [participants odds ratio (OR) 9.8; researchers OR 4.9]. Participants and researchers also reported many dependent links (80%, 66%, respectively), most frequently relational links (75%, 64%), followed by content (60%, 25%) and identity links (51%, 22%).

Conclusion: Trauma appears to be a strong shaping force for voice content and its psychological impact. The most common trauma-voice links involved the experience of cognitive-affective psychological threat, embodied in relational experiences. Trauma-induced mechanisms may be important intervention targets.
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http://dx.doi.org/10.1017/S0033291721004955DOI Listing
January 2022

Characteristics and stability of hallucinations and delusions in patients with borderline personality disorder.

Compr Psychiatry 2022 02 17;113:152290. Epub 2021 Dec 17.

Department of Clinical Psychology and Amsterdam Public Health Research Institute, VU University, Amsterdam, the Netherlands.

Background: Psychotic features have been part of the description of the borderline personality disorder (BPD) ever since the concept "borderline" was introduced. However, there is still much to learn about the presence and characteristics of delusions and about the stability of both hallucinations and delusions in patients with BPD.

Methods: A follow-up study was conducted in 326 BPD outpatients (median time between baseline and follow-up = 3.16 years). Data were collected via telephone (n = 267) and face-to-face interviews (n = 60) including the Comprehensive Assessment of Symptoms and History interview, Positive And Negative Syndrome Scale and the Psychotic Symptom Rating Scale.

Results: The point prevalence of delusions was 26%, with a median strong delusion conviction. For the group as a whole, the presence and severity of both hallucinations and delusions was found to be stable at follow-up. Participants with persistent hallucinations experienced more comorbid psychiatric disorders, and they differed from those with intermittent or sporadic hallucinations with their hallucinations being characterized by a higher frequency, causing a higher intensity of distress and more disruption in daytime or social activities.

Conclusions: Delusions in patients with BPD occur frequently and cause distress. Contrary to tenacious beliefs, hallucinations and delusions in participants with BPD are often present in an intermittent or persistent pattern. Persistent hallucinations can be severe, causing disruption of life. Overall, we advise to refrain from terms such as "pseudo", or assume transience when encountering psychotic phenomena in patients with BPD, but rather to carefully assess these experiences and initiate a tailor-made treatment plan.
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http://dx.doi.org/10.1016/j.comppsych.2021.152290DOI Listing
February 2022

Corrigendum to: Cross Validation of the Prodromal Questionnaire 16-Item Version in an Adolescent Help-Seeking Population.

Schizophr Bull Open 2021 Jan 18;2(1):sgab021. Epub 2021 Sep 18.

Parnassia Psychiatric Institute, Rotterdam and The Hague, the Netherlands.

[This corrects the article DOI: 10.1093/schizbullopen/sgaa033.].
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http://dx.doi.org/10.1093/schizbullopen/sgab021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8650071PMC
January 2021

Momentary Manifestations of Negative Symptoms as Predictors of Clinical Outcomes in People at High Risk for Psychosis: Experience Sampling Study.

JMIR Ment Health 2021 11 19;8(11):e30309. Epub 2021 Nov 19.

Department of Public Mental Health, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

Background: Negative symptoms occur in individuals at ultrahigh risk (UHR) for psychosis. Although there is evidence that observer ratings of negative symptoms are associated with level of functioning, the predictive value of subjective experience in daily life for individuals at UHR has not been studied yet.

Objective: This study therefore aims to investigate the predictive value of momentary manifestations of negative symptoms for clinical outcomes in individuals at UHR.

Methods: Experience sampling methodology was used to measure momentary manifestations of negative symptoms (blunted affective experience, lack of social drive, anhedonia, and social anhedonia) in the daily lives of 79 individuals at UHR. Clinical outcomes (level of functioning, illness severity, UHR status, and transition status) were assessed at baseline and at 1- and 2-year follow-ups.

Results: Lack of social drive, operationalized as greater experienced pleasantness of being alone, was associated with poorer functioning at the 2-year follow-up (b=-4.62, P=.01). Higher levels of anhedonia were associated with poorer functioning at the 1-year follow-up (b=5.61, P=.02). Higher levels of social anhedonia were associated with poorer functioning (eg, disability subscale: b=6.36, P=.006) and greater illness severity (b=-0.38, P=.045) at the 1-year follow-up. In exploratory analyses, there was evidence that individuals with greater variability of positive affect (used as a measure of blunted affective experience) experienced a shorter time to remission from UHR status at follow-up (hazard ratio=4.93, P=.005).

Conclusions: Targeting negative symptoms in individuals at UHR may help to predict clinical outcomes and may be a promising target for interventions in the early stages of psychosis.
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http://dx.doi.org/10.2196/30309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8663470PMC
November 2021

Satisfaction with social connectedness as a predictor for positive and negative symptoms of psychosis: A PHAMOUS study.

Schizophr Res 2021 12 13;238:121-127. Epub 2021 Oct 13.

Lentis Psychiatric Institute, Hereweg 80, 9725 AG Groningen, the Netherlands; University of Groningen, Faculty of Behavioral and Social Sciences, Grote Kruisstraat 2/1, 9712 TS Groningen, the Netherlands; University of Groningen, University Medical Center Groningen, University Center for Psychiatry, Rob Giel Research Center, P.O. 30.001, 9700 RB, Groningen, the Netherlands. Electronic address:

Purpose: This study examines satisfaction with social connectedness (SSC) as predictor of positive and negative symptoms in people with a psychotic disorder.

Methods: Data from the Pharmacotherapy Monitoring and Outcome Survey (PHAMOUS) was used from patients assessed between 2014 and 2019, diagnosed with a psychotic disorder (N = 2109). Items about social connectedness of the Manchester short assessment of Quality of Life (ManSA) were used to measure SSC. Linear mixed models were used to estimate the association of SSC with the Positive and Negative Syndrome Scale (PANSS) after one and two years against α = 0.01. Analyses were adjusted for symptoms, time since onset, gender and age. Additionally, fluctuation of positive and negative symptom scores over time was estimated.

Results: The mean duration of illness of the sample was 18.8 years (SD 10.7) with >65% showing only small variation in positive and negative symptoms over a two to five-year time period. After adjustment for covariates, SSC showed to be negatively associated with positive symptoms after one year (β = -0.47, p < 0.001, 95% CI = -0.70, -025) and two years (β = -0.59, p < 0.001, 95% CI = -0.88, -0.30), and for negative symptoms after one year (β = -0.52, p < 0.001, 95% CI = -0.77, -0.27). The prediction of negative symptoms was not significant at two years.

Conclusion: This research indicates that interventions on SSC might positively impact mental health for people with psychosis. SSC is a small and robust predictor of future levels of positive symptoms. Negative symptoms could be predicted by SSC at one year.
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http://dx.doi.org/10.1016/j.schres.2021.10.004DOI Listing
December 2021

Impact of smoking Behavior on cognitive functioning in persons at risk for psychosis and healthy controls: A longitudinal study.

Eur Psychiatry 2021 09 21;64(1):e60. Epub 2021 Sep 21.

Department of Psychiatry, Amsterdam UMC (location AMC), Amsterdam, The Netherlands.

Background: The high prevalence of smoking in individuals who are at ultra-high risk (UHR) for psychosis is well known and moderate cognitive deficits have also been found in UHR. However, the association between smoking and cognition in UHR is unknown and longitudinal studies are lacking.

Method: A cohort study with 330 UHR individuals and 66 controls was conducted, as part of the European network of national schizophrenia networks studying gene-environment interactions (EU-GEI). At baseline and after 6, 12, and 24 months, smoking behavior was assessed with the Composite International Diagnostic Interview and cognitive functioning with a comprehensive test battery. Linear mixed-effects analyses were used to examine the multicross-sectional and prospective associations between (change in) smoking behavior and cognitive functioning, accounting for confounding variables.

Results: At baseline, 53% of UHR and 27% of controls smoked tobacco. Smoking UHR and controls did not significantly differ from nonsmoking counterparts on the tested cognitive domains (speed of processing, attention/vigilance, working memory, verbal learning, or reasoning/problem solving) across different assessment times. Neither smoking cessation nor initiation was associated with a significant change in cognitive functioning in UHR.

Conclusions: No associations were found between smoking and cognitive impairment in UHR nor in controls. However, the fact that one in every two UHR individuals report daily use of tobacco is alarming. Our data suggest that UHR have fewer cognitive impairments and higher smoking cessation rates compared to patients with first-episode psychosis found in literature. Implications to promote smoking cessation in the UHR stage need further investigation.
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http://dx.doi.org/10.1192/j.eurpsy.2021.2233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8516743PMC
September 2021

Efficacy of a transdiagnostic ecological momentary intervention for improving self-esteem (SELFIE) in youth exposed to childhood adversity: study protocol for a multi-center randomized controlled trial.

Trials 2021 Sep 19;22(1):641. Epub 2021 Sep 19.

Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.

Background: Targeting low self-esteem in youth exposed to childhood adversity is a promising strategy for preventing adult mental disorder, but psychological help remains difficult to access and accept for youth, calling for novel, youth-friendly approaches. Mobile Health (mHealth) and, most prominently, ecological momentary interventions (EMIs) provide a unique opportunity to deliver youth-friendly, personalized, real-time, guided self-help interventions. The aim of this study is to investigate the efficacy of a novel, accessible, transdiagnostic ecological momentary intervention for improving self-esteem ('SELFIE') in youth with prior exposure to childhood adversity.

Methods/design: In a parallel-group, assessor-blind, multi-center randomized controlled trial, individuals aged 12-26 years with prior exposure to childhood adversity and low self-esteem will be randomly allocated to SELFIE in addition to treatment as usual (TAU) as the experimental condition or the control condition of TAU only, which will include access to all standard health care. SELFIE is a digital guided self-help intervention administered through a smartphone-based app to allow for interactive, personalized, real-time and real-world transfer of intervention components in individuals' daily lives, blended with three training sessions delivered by trained mental health professionals over a 6-week period. Outcomes will be assessed at baseline, post-intervention, and 6-month follow-up by blinded assessors. The primary outcome will be the level of self-esteem as measured with the Rosenberg Self-Esteem Scale (RSES).

Discussion: The current study is the first to establish the efficacy of an EMI focusing on improving self-esteem transdiagnostically in youth exposed to childhood adversity. If this trial provides evidence on the efficacy of SELFIE, it has significant potential to contribute to minimizing the deleterious impact of childhood adversity and, thereby, preventing the development of mental disorder later in life.

Trial Registration: Netherlands Trial Register NL7129 (NTR7475 ). Registered on 9 November 2018.
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http://dx.doi.org/10.1186/s13063-021-05585-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8449997PMC
September 2021

Impact of Comorbid Affective Disorders on Longitudinal Clinical Outcomes in Individuals at Ultra-high Risk for Psychosis.

Schizophr Bull 2022 01;48(1):100-110

Department of Psychiatry, Amsterdam University Medical Center, Meibergdreef, University of Amsterdam, Amsterdam, the Netherlands.

Introduction: Diagnoses of anxiety and/or depression are common in subjects at Ultra-High Risk for Psychosis (UHR) and associated with extensive functional impairment. Less is known about the impact of affective comorbidities on the prospective course of attenuated psychotic symptoms (APS).

Method: Latent class mixed modelling identified APS trajectories in 331 UHR subjects assessed at baseline, 6, 12, and 24 months follow-up. The prognostic value of past, baseline, and one-year DSM-IV depressive or anxiety disorders on trajectories was investigated using logistic regression, controlling for confounders. Cox proportional hazard analyses investigated associations with transition risk.

Results: 46.8% of participants fulfilled the criteria for a past depressive disorder, 33.2% at baseline, and 15.1% at one-year follow-up. Any past, baseline, or one-year anxiety disorder was diagnosed in 42.9%, 37.2%, and 27.0%, respectively. Participants were classified into one of three latent APS trajectory groups: (1) persistently low, (2) increasing, and (3) decreasing. Past depression was associated with a higher risk of belonging to the increasing trajectory group, compared to the persistently low (OR = 3.149, [95%CI: 1.298-7.642]) or decreasing group (OR = 3.137, [1.165-8.450]). In contrast, past (OR = .443, [.179-1.094]) or current (OR = .414, [.156-1.094]) anxiety disorders showed a trend-level association with a lower risk of belonging to the increasing group compared to the persistently low group. Past depression was significantly associated with a higher risk of transitioning to psychosis (HR = 2.123, [1.178-3.828]).

Conclusion: A past depressive episode might be a particularly relevant risk factor for an unfavorable course of APS in UHR individuals. Early affective disturbances may be used to advance detection, prognostic, and clinical strategies.
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http://dx.doi.org/10.1093/schbul/sbab088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8781381PMC
January 2022

Association between tobacco use and symptomatology in individuals at ultra-high risk to develop a psychosis: A longitudinal study.

Schizophr Res 2021 10 11;236:48-53. Epub 2021 Aug 11.

Amsterdam UMC (location AMC), Department of Psychiatry, Amsterdam, the Netherlands.

Background: The high prevalence rates and impact of tobacco smoking in individuals with a psychotic disorder have become an increasing interest. Little is known about tobacco smoking in individuals at ultra-high risk of psychosis (UHR).

Methods: We studied 345 UHR individuals of the high-risk study of the European network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI). Smoking status and the number of cigarettes per day were assessed at multiple moments using the CIDI. Symptom severity at each time point was assessed using CAARMS. Linear mixed-effects analyses were conducted to examine the multi-cross-sectional and prospective associations between (change in) smoking behaviour and symptomatology.

Findings: At baseline, 175 individuals (53%) smoked tobacco with an average of 12.4 (SD = 9.0) cigarettes per day. Smokers did not significantly differ in symptom severity from non-smokers on general, positive, negative, emotional, cognitive, behavioural, or motor symptoms across time. However, associations were found between the number of cigarettes and the severity of general psychopathology (estimate 0.349, SE 0.146, p = 0.017). Change in the number of cigarettes had no significant effect on change in general symptom severity (estimate 0.330, SE 0.285, p = 0.248).

Interpretation: Smoking prevalence in UHR individuals is high. Cigarette consumption was associated with higher levels of general symptoms. However, we observed no association between change in number of cigarettes and symptom severity. Given the fact that smoking is associated with poorer health and worse outcomes in people with psychosis, the clinical high-risk phase offers a window of opportunity for prevention and cessation interventions.
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http://dx.doi.org/10.1016/j.schres.2021.08.006DOI Listing
October 2021

Voice-hearers' beliefs about the causes of their voices.

Psychiatry Res 2021 08 13;302:113997. Epub 2021 May 13.

Department of Clinical Psychology, VU University and Amsterdam Public Health Research, van der Boechorststraat 7, 1081 BT Amsterdam, the Netherlands; Parnassia Psychiatric Institute, Zoutkeetsingel 40, 2512 HN The Hague, the Netherlands.

Despite empirical evidence for multifactorial causes of voice-hearing, people's own beliefs about what caused their voices are understudied. People with distressing voices (n=125) completed measures of trauma, post-traumatic stress disorder (PTSD) symptoms, and beliefs about causality. Most participants reported trauma in the past (97%) and PTSD symptoms were prevalent. Traumatic experiences were the most commonly endorsed causal factor of voice-hearing (64%), followed by distress (62%). Beliefs about biological causes, including drug use (22%), were least endorsed. Those who experienced more traumatic events and more PTSD symptoms were more likely to endorse trauma as a causal factor of voice-hearing (R=0.38).
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http://dx.doi.org/10.1016/j.psychres.2021.113997DOI Listing
August 2021

Detection of Domestic Violence and Abuse by Community Mental Health Teams Using the BRAVE Intervention: A Multicenter, Cluster Randomized Controlled Trial.

J Interpers Violence 2022 Aug 18;37(15-16):NP14310-NP14336. Epub 2021 Apr 18.

Erasmus University Medical Centre Rotterdam, the Netherlands.

Despite increased prevalence of domestic violence and abuse (DVA), victimization through DVA often remains undetected in mental health care. To estimate the effectiveness of a system provider level training intervention by comparing the detection and referral rates of DVA of intervention community mental health (CMH) teams with rates in control CMH teams. We also aimed to determine whether improvements in knowledge, skills and attitudes to DVA were greater in clinicians working in intervention CMH teams than those working in control teams. We conducted a cluster randomized controlled trial in two urban areas of the Netherlands. Detection and referral rates were assessed at baseline and at 6 and 12 months after the start of the intervention. DVA knowledge, skills and attitudes were assessed using a survey at baseline and at 6 and 12 months after start of the intervention. Electronic patient files were used to identify detected and referred cases of DVA. Outcomes were compared between the intervention and control teams using a generalized linear mixed model. During the 12-month follow-up, detection and referral rates did not differ between the intervention and control teams. However, improvements in knowledge, skills and attitude during that follow-up period were greater in intervention teams than in control teams: β 3.21 (95% CI 1.18-4.60). Our trial showed that a training program on DVA knowledge and skills in CMH teams can increase knowledge and attitude towards DVA. However, our intervention does not appear to increase the detection or referral rates of DVA in patients with a severe mental illness. A low detection rate of DVA remains a major problem. Interventions with more obligatory elements and a focus on improving communication between CMH teams and DVA services are recommended.
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http://dx.doi.org/10.1177/08862605211004177DOI Listing
August 2022

Preventive interventions for individuals at ultra high risk for psychosis: An updated and extended meta-analysis.

Clin Psychol Rev 2021 06 26;86:102005. Epub 2021 Mar 26.

Orygen, Parkville, VIC, Australia; Centre for Youth Mental Health, The University of Melbourne, Parkville, VIC, Australia. Electronic address:

Intervention at the earliest illness stage, in ultra or clinical high-risk individuals, or indicated prevention, currently represents the most promising strategy to ameliorate, delay or prevent psychosis. We review the current state of evidence and conduct a broad-spectrum meta-analysis of various outcomes: transition to psychosis, attenuated positive and negative psychotic symptoms, mania, depression, anxiety, general psychopathology, symptom-related distress, functioning, quality of life, and treatment acceptability. 26 randomized controlled trials were included. Meta-analytically pooled interventions reduced transition rate (risk ratio [RR] = 0.57, 95%CI 0.41-0.81) and attenuated positive psychotic symptoms at 12-months (standardized mean difference = -0.15, 95%CI = -0.28--0.01). When stratified by intervention type (pharmacological, psychological), only the pooled effect of psychological interventions on transition rate was significant. Cognitive behavioral therapy (CBT) was associated with a reduction in incidence at 12-months (RR = 0.52, 95%CI = 0.33-0.82) and 18-48-months (RR = 0.60, 95%CI = 0.42-0.84), but not 6-months. Findings at 12-months and 18-48-months were robust in sensitivity and subgroup analyses. All other outcomes were non-significant. To date, effects of trialed treatments are specific to transition and, a lesser extent, attenuated positive symptoms, highlighting the future need to target other symptom domains and functional outcomes. Sound evidence supports CBT in reducing transition and the value of intervening at this illness stage. STUDY REGISTRATION: Research Registry ID: reviewregistry907.
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http://dx.doi.org/10.1016/j.cpr.2021.102005DOI Listing
June 2021

The associations between migrant status and ethnicity and the identification of individuals at ultra-high risk for psychosis and transition to psychosis: a systematic review.

Soc Psychiatry Psychiatr Epidemiol 2021 Nov 28;56(11):1923-1941. Epub 2021 Feb 28.

Orygen, 35 Poplar Rd, Parkville, Melbourne, VIC, 3052, Australia.

Purpose: Migrant and ethnic minority populations exhibit a higher incidence of psychotic disorders. The Ultra-High Risk for psychosis (UHR) paradigm provides an opportunity to explore the stage at which such factors influence the development of psychosis. In this systematic review, we collate and appraise the literature on the association between ethnicity and migrant status and the rate of identification of individuals at UHR, as well as their rate of transition to psychosis.

Methods: We conducted a systematic review in the Ovid Medline, PsychINFO, Pubmed, CINAHL and EMBASE databases according to PRISMA guidelines. We included studies written in English that included an UHR cohort, provided a measure of ethnicity or migrant status, and examined the incidence, rate, or risk of UHR identification or transition to psychosis.

Results: Of 2182 unique articles identified, seven fulfilled the criteria. One study found overrepresentation of UHR individuals from black ethnic groups, while another found underrepresentation. Two studies found increased rates of transition among certain ethnic groups and a further two found no association. Regarding migrant status, one study found that first-generation migrants were underrepresented in an UHR sample. Lastly, a lower transition rate in migrant populations was identified in one study, while two found no association.

Conclusion: Rates of UHR identification and transition according to ethnic and migrant status were inconsistent and insufficient to conclusively explain higher incidences of psychotic disorders among these groups. We discuss the clinical implications and avenues for future research, which is required to clarify the nature of the associations.
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http://dx.doi.org/10.1007/s00127-021-02047-3DOI Listing
November 2021

Obsessive-Compulsive Symptoms and Other Symptoms of the At-risk Mental State for Psychosis: A Network Perspective.

Schizophr Bull 2021 07;47(4):1018-1028

Department of Psychology, Psychological Methods, University of Amsterdam, Amsterdam, the Netherlands.

Background: The high prevalence of obsessive-compulsive symptoms (OCS) among subjects at Ultra-High Risk (UHR) for psychosis is well documented. However, the network structure spanning the relations between OCS and symptoms of the at risk mental state for psychosis as assessed with the Comprehensive Assessment of At Risk Mental States (CAARMS) has not yet been investigated. This article aimed to use a network approach to investigate the associations between OCS and CAARMS symptoms in a large sample of individuals with different levels of risk for psychosis.

Method: Three hundred and forty-one UHR and 66 healthy participants were included, who participated in the EU-GEI study. Data analysis consisted of constructing a network of CAARMS symptoms, investigating central items in the network, and identifying the shortest pathways between OCS and positive symptoms.

Results: Strong associations between OCS and anxiety, social isolation and blunted affect were identified. Depression was the most central symptom in terms of the number of connections, and anxiety was a key item in bridging OCS to other symptoms. Shortest paths between OCS and positive symptoms revealed that unusual thought content and perceptual abnormalities were connected mainly via anxiety, while disorganized speech was connected via blunted affect and cognitive change.

Conclusions: Findings provide valuable insight into the central role of depression and the potential connective component of anxiety between OCS and other symptoms of the network. Interventions specifically aimed to reduce affective symptoms might be crucial for the development and prospective course of symptom co-occurrence.
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http://dx.doi.org/10.1093/schbul/sbaa187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266672PMC
July 2021

UP'S: A Cohort Study on Recovery in Psychotic Disorder Patients: Design Protocol.

Front Psychiatry 2020 12;11:609530. Epub 2021 Jan 12.

Department of Psychiatry, Erasmus MC, Epidemiological and Social Psychiatric Research Institute, Rotterdam, Netherlands.

Recovery is a multidimensional concept, including symptomatic, functional, social, as well as personal recovery. The present study aims at exploring psychosocial and biological determinants of personal recovery, and disentangling time-dependent relationships between personal recovery and the other domains of recovery in a sample of people with a psychotic disorder. A cohort study is conducted with a 10-year follow-up. Personal recovery is assessed using the Recovering Quality of Life Questionnaire (ReQoL) and the Individual Recovery Outcomes Counter (I.ROC). Other domains of recovery are assessed by the Positive and Negative Symptom Scale Remission (PANSS-R), the BRIEF-A and the Social Role Participation Questionnaire-Short version (SRPQ) to assess symptomatic, functional and societal recovery, respectively. In addition, multiple biological, psychological, and social determinants are assessed. This study aims to assess the course of personal recovery, and to find determinants and time-dependent relationships with symptomatic, functional and societal recovery in people with a psychotic disorder. Strengths of the study are the large number of participants, long duration of follow-up, multiple assessments over time, extending beyond the treatment trajectory, and the use of a broad range of biological, psychological, and social determinants.
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http://dx.doi.org/10.3389/fpsyt.2020.609530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874019PMC
January 2021

Cognitive functioning throughout adulthood and illness stages in individuals with psychotic disorders and their unaffected siblings.

Mol Psychiatry 2021 08 7;26(8):4529-4543. Epub 2021 Jan 7.

Department of Psychiatry, Dokuz Eylül University, School of Medicine, Izmir, Turkey.

Important questions remain about the profile of cognitive impairment in psychotic disorders across adulthood and illness stages. The age-associated profile of familial impairments also remains unclear, as well as the effect of factors, such as symptoms, functioning, and medication. Using cross-sectional data from the EU-GEI and GROUP studies, comprising 8455 participants aged 18 to 65, we examined cognitive functioning across adulthood in patients with psychotic disorders (n = 2883), and their unaffected siblings (n = 2271), compared to controls (n = 3301). An abbreviated WAIS-III measured verbal knowledge, working memory, visuospatial processing, processing speed, and IQ. Patients showed medium to large deficits across all functions (ES range = -0.45 to -0.73, p < 0.001), while siblings showed small deficits on IQ, verbal knowledge, and working memory (ES = -0.14 to -0.33, p < 0.001). Magnitude of impairment was not associated with participant age, such that the size of impairment in older and younger patients did not significantly differ. However, first-episode patients performed worse than prodromal patients (ES range = -0.88 to -0.60, p < 0.001). Adjusting for cannabis use, symptom severity, and global functioning attenuated impairments in siblings, while deficits in patients remained statistically significant, albeit reduced by half (ES range = -0.13 to -0.38, p < 0.01). Antipsychotic medication also accounted for around half of the impairment in patients (ES range = -0.21 to -0.43, p < 0.01). Deficits in verbal knowledge, and working memory may specifically index familial, i.e., shared genetic and/or shared environmental, liability for psychotic disorders. Nevertheless, potentially modifiable illness-related factors account for a significant portion of the cognitive impairment in psychotic disorders.
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http://dx.doi.org/10.1038/s41380-020-00969-zDOI Listing
August 2021

The association between migrant status and transition in an ultra-high risk for psychosis population.

Soc Psychiatry Psychiatr Epidemiol 2021 Jun 5;56(6):943-952. Epub 2021 Jan 5.

Department of Psychiatry, University Hospital Jena, Jena, Germany.

Purpose: Migrant status is one of the most replicated and robust risk factors for developing a psychotic disorder. This study aimed to determine whether migrant status in people identified as Ultra-High Risk for Psychosis (UHR) was associated with risk of transitioning to a full-threshold psychotic disorder.

Methods: Hazard ratios for the risk of transition were calculated from five large UHR cohorts (n = 2166) and were used to conduct a meta-analysis using the generic inverse-variance method using a random-effects model.

Results: 2166 UHR young people, with a mean age of 19.1 years (SD ± 4.5) were included, of whom 221 (10.7%) were first-generation migrants. A total of 357 young people transitioned to psychosis over a median follow-up time of 417 days (I.Q.R.147-756 days), representing 17.0% of the cohort. The risk of transition to a full-threshold disorder was not increased for first-generation migrants, (HR = 1.08, 95% CI 0.62-1.89); however, there was a high level of heterogeneity between studies The hazard ratio for second-generation migrants to transition to a full-threshold psychotic disorder compared to the remainder of the native-born population was 1.03 (95% CI 0.70-1.51).

Conclusions: This meta-analysis did not find a statistically significant association between migrant status and an increased risk for transition to a full-threshold psychotic disorder; however, several methodological issues could explain this finding. Further research should focus on examining the risk of specific migrant groups and also ensuring that migrant populations are adequately represented within UHR clinics.
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http://dx.doi.org/10.1007/s00127-020-02012-6DOI Listing
June 2021

Assessing the Acceptability, Feasibility and Sustainability of an Intervention to Increase Detection of Domestic Violence and Abuse in Patients Suffering From Severe Mental Illness: A Qualitative Study.

Front Psychiatry 2020 28;11:581031. Epub 2020 Oct 28.

Department of Psychiatry, Epidemiological and Social Psychiatric Research Institute, Erasmus University Medical Centre Rotterdam, Rotterdam, Netherlands.

Despite interventions to improve detection rates, domestic violence, and abuse (DVA) remains largely undetected by healthcare services. We therefore aimed to examine the acceptability, feasibility, and sustainability of an intervention aiming to improve DVA detection rates, which included a clear referral pathway (i.e., the BRAVE intervention) and to explore the acceptability and feasibility of DVA management and referrals in general, in the context of low detection rates. Qualitative study design with four focus groups of 16 community mental health (CMH) clinicians from both control and intervention arms. The focus groups discussed managing DVA in clinical practice and staff experiences with the BRAVE intervention in particular. Focus groups continued until saturation of the subject was reached. Interviews were analyzed using a thematic analysis approach. DVA was seen to be highly relevant to mental healthcare but is also a very sensitive subject. Barriers in CMH professionals, institutions, and society meant CMH professionals often refrained from asking about DVA in patients. Barriers included communication difficulties between CMH professionals and DVA professionals, a fear of disrupting the therapeutic alliance with the patient, and a lack of appropriate services to help victims of DVA. The BRAVE intervention was acceptable but not feasible or sustainable. Personal, institutional, and public barriers make it not feasible for CMH professionals to detect DVA in mental healthcare. To increase the detection of DVA, professional standards should be combined with training, feedback sessions with peers and DVA counselors, and routine enquiry about DVA. ISRCTN, trial registration number: ISRCTN14115257.
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http://dx.doi.org/10.3389/fpsyt.2020.581031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655979PMC
October 2020

Clinical, cognitive and neuroanatomical associations of serum NMDAR autoantibodies in people at clinical high risk for psychosis.

Mol Psychiatry 2021 06 19;26(6):2590-2604. Epub 2020 Oct 19.

Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's Health Partners, King's College London, London, UK.

Serum neuronal autoantibodies, such as those to the NMDA receptor (NMDAR), are detectable in a subgroup of patients with psychotic disorders. It is not known if they are present before the onset of psychosis or whether they are associated with particular clinical features or outcomes. In a case-control study, sera from 254 subjects at clinical high risk (CHR) for psychosis and 116 healthy volunteers were tested for antibodies against multiple neuronal antigens implicated in CNS autoimmune disorders, using fixed and live cell-based assays (CBAs). Within the CHR group, the relationship between NMDAR antibodies and symptoms, cognitive function and clinical outcomes over 24 month follow-up was examined. CHR subjects were not more frequently seropositive for neuronal autoantibodies than controls (8.3% vs. 5.2%; OR = 1.50; 95% CI: 0.58-3.90). The NMDAR was the most common target antigen and NMDAR IgGs were more sensitively detected with live versus fixed CBAs (p < 0.001). Preliminary phenotypic analyses revealed that within the CHR sample, the NMDAR antibody seropositive subjects had higher levels of current depression, performed worse on the Rey Auditory Verbal Learning Task (p < 0.05), and had a markedly lower IQ (p < 0.01). NMDAR IgGs were not more frequent in subjects who later became psychotic than those who did not. NMDAR antibody serostatus and titre was associated with poorer levels of functioning at follow-up (p < 0.05) and the presence of a neuronal autoantibody was associated with larger amygdala volumes (p < 0.05). Altogether, these findings demonstrate that NMDAR autoantibodies are detectable in a subgroup of CHR subjects at equal rates to controls. In the CHR group, they are associated with affective psychopathology, impairments in verbal memory, and overall cognitive function: these findings are qualitatively and individually similar to core features of autoimmune encephalitis and/or animal models of NMDAR antibody-mediated CNS disease. Overall the current work supports further evaluation of NMDAR autoantibodies as a possible prognostic biomarker and aetiological factor in a subset of people already meeting CHR criteria.
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http://dx.doi.org/10.1038/s41380-020-00899-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8440194PMC
June 2021

Relationship between jumping to conclusions and clinical outcomes in people at clinical high-risk for psychosis.

Psychol Med 2022 06 6;52(8):1569-1577. Epub 2020 Oct 6.

Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.

Background: Psychosis is associated with a reasoning bias, which manifests as a tendency to 'jump to conclusions'. We examined this bias in people at clinical high-risk for psychosis (CHR) and investigated its relationship with their clinical outcomes.

Methods: In total, 303 CHR subjects and 57 healthy controls (HC) were included. Both groups were assessed at baseline, and after 1 and 2 years. A 'beads' task was used to assess reasoning bias. Symptoms and level of functioning were assessed using the Comprehensive Assessment of At-Risk Mental States scale (CAARMS) and the Global Assessment of Functioning (GAF), respectively. During follow up, 58 (16.1%) of the CHR group developed psychosis (CHR-T), and 245 did not (CHR-NT). Logistic regressions, multilevel mixed models, and Cox regression were used to analyse the relationship between reasoning bias and transition to psychosis and level of functioning, at each time point.

Results: There was no association between reasoning bias at baseline and the subsequent onset of psychosis. However, when assessed after the transition to psychosis, CHR-T participants showed a greater tendency to jump to conclusions than CHR-NT and HC participants (55, 17, 17%; χ2 = 8.13, = 0.012). There was a significant association between jumping to conclusions (JTC) at baseline and a reduced level of functioning at 2-year follow-up in the CHR group after adjusting for transition, gender, ethnicity, age, and IQ.

Conclusions: In CHR participants, JTC at baseline was associated with adverse functioning at the follow-up. Interventions designed to improve JTC could be beneficial in the CHR population.
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http://dx.doi.org/10.1017/S0033291720003396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9226382PMC
June 2022
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