The relationship between cognitive functioning and psychopathology in patients with psychiatric disorders: a transdiagnostic network analysis.

BACKGROUND: Patients with psychiatric disorders often experience cognitive dysfunction, but the precise relationship between cognitive deficits and psychopathology remains unclear. We investigated the relationships between domains of cognitive functioning and psychopathology in a transdiagnostic sample using a data-driven approach. METHODS: Cross-sectional network analyses were conducted to investigate the relationships between domains of psychopathology and cognitive functioning and detect clusters in the network. This naturalistic transdiagnostic sample consists of 1016 psychiatric patients who have a variety of psychiatric diagnoses, such as depressive disorders, anxiety disorders, obsessive-compulsive and related disorders, and schizophrenia spectrum and other psychotic disorders. Psychopathology symptoms were assessed using various questionnaires. Core cognitive domains were assessed with a battery of automated tests. RESULTS: Network analysis detected three clusters that we labelled: general psychopathology, substance use, and cognition. Depressive and anxiety symptoms, verbal memory, and visual attention were the most central nodes in the network. Most associations between cognitive functioning and symptoms were negative, i.e. increased symptom severity was associated with worse cognitive functioning. Cannabis use, (subclinical) psychotic experiences, and anhedonia had the strongest total negative relationships with cognitive variables. CONCLUSIONS: Cognitive functioning and psychopathology are independent but related dimensions, which interact in a transdiagnostic manner. Depression, anxiety, verbal memory, and visual attention are especially relevant in this network and can be considered independent transdiagnostic targets for research and treatment in psychiatry. Moreover, future research on cognitive functioning in psychopathology should take a transdiagnostic approach, focusing on symptom-specific interactions with cognitive domains rather than investigating cognitive functioning within diagnostic categories.

The association of plasma inflammatory markers with omega-3 fatty acids and their mediating role in psychotic symptoms and functioning: An analysis of the NEURAPRO clinical trial.

BACKGROUND: There is increasing evidence that dysregulation of polyunsaturated fatty acids (FAs) mediated membrane function plays a role in the pathophysiology of schizophrenia. Even though preclinical findings have supported the anti-inflammatory properties of omega-3 FAs on brain health, their biological roles as anti-inflammatory agents and their therapeutic role on clinical symptoms of psychosis risk are not well understood. In the current study, we investigated the relationship of erythrocyte omega-3 FAs with plasma immune markers in a clinical high risk for psychosis (CHR) sample. In addition, a mediation analysis was performed to examine whether previously reported associations between omega-3 FAs and clinical outcomes were mediated via plasma immune markers. Clinical outcomes for CHR participants in the NEURAPRO clinical trial were measured using the Brief Psychiatric Rating Scale (BPRS), Schedule for the Scale of Assessment of Negative Symptoms (SANS) and Social and Occupational Functioning Assessment Scale (SOFAS) scales. The erythrocyte omega-3 index [eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA)] and plasma concentrations of inflammatory markers were quantified at baseline (n = 268) and 6 month follow-up (n = 146) by gas chromatography and multiplex immunoassay, respectively. In linear regression models, the baseline plasma concentrations of Interleukin (IL)-15, Intercellular adhesion molecule (ICAM)-1 and Vascular cell adhesion molecule (VCAM)-1 were negatively associated with baseline omega-3 index. In addition, 6-month change in IL-12p40 and TNF-α showed a negative association with change in omega-3 index. In longitudinal analyses, the baseline and 6 month change in omega-3 index was negatively associated with VCAM-1 and TNF-α respectively at follow-up. Mediation analyses provided little evidence for mediating effects of plasma immune markers on the relationship between omega-3 FAs and clinical outcomes (psychotic symptoms and functioning) in CHR participants. Our results indicate a predominantly anti-inflammatory relationship of omega-3 FAs on plasma inflammatory status in CHR individuals, but this did not appear to convey clinical benefits at 6 month and 12 month follow-up. Both immune and non-immune biological effects of omega-3 FAs would be resourceful in understanding the clinical benefits of omega-3 FAs in CHR papulation.

Machine learning based prediction and the influence of complement - Coagulation pathway proteins on clinical outcome: Results from the NEURAPRO trial.

BACKGROUND: Functional outcomes are important measures in the overall clinical course of psychosis and individuals at clinical high-risk (CHR), however, prediction of functional outcome remains difficult based on clinical information alone. In the first part of this study, we evaluated whether a combination of biological and clinical variables could predict future functional outcome in CHR individuals. The complement and coagulation pathways have previously been identified as being of relevance to the pathophysiology of psychosis and have been found to contribute to the prediction of clinical outcome in CHR participants. Hence, in the second part we extended the analysis to evaluate specifically the relationship of complement and coagulation proteins with psychotic symptoms and functional outcome in CHR. MATERIALS AND METHODS: We carried out plasma proteomics and measured plasma cytokine levels, and erythrocyte membrane fatty acid levels in a sub-sample (n = 158) from the NEURAPRO clinical trial at baseline and 6 months follow up. Functional outcome was measured using Social and Occupational Functional assessment Score (SOFAS) scale. Firstly, we used support vector machine learning techniques to develop predictive models for functional outcome at 12 months. Secondly, we developed linear regression models to understand the association between 6-month follow-up levels of complement and coagulation proteins with 6-month follow-up measures of positive symptoms summary (PSS) scores and functional outcome. RESULTS AND CONCLUSION: A prediction model based on clinical and biological data including the plasma proteome, erythrocyte fatty acids and cytokines, poorly predicted functional outcome at 12 months follow-up in CHR participants. In linear regression models, four complement and coagulation proteins (coagulation protein X, Complement C1r subcomponent like protein, Complement C4A & Complement C5) indicated a significant association with functional outcome; and two proteins (coagulation factor IX and complement C5) positively associated with the PSS score. Our study does not provide support for the utility of cytokines, proteomic or fatty acid data for prediction of functional outcomes in individuals at high-risk for psychosis. However, the association of complement protein levels with clinical outcome suggests a role for the complement system and the activity of its related pathway in the functional impairment and positive symptom severity of CHR patients.

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

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.

Protocol Across study: longitudinal transdiagnostic cognitive functioning, psychiatric symptoms, and biological parameters in patients with a psychiatric disorder.

BACKGROUND: Patients with psychiatric disorders, such as major depressive disorder, schizophrenia or obsessive-compulsive disorder, often suffer from cognitive dysfunction. The nature of these dysfunctions and their relation with clinical symptoms and biological parameters is not yet clear. Traditionally, cognitive dysfunction is studied in patients with specific psychiatric disorders, disregarding the fact that cognitive deficits are shared across disorders. The Across study aims to investigate cognitive functioning and its relation with psychiatric symptoms and biological parameters transdiagnostically and longitudinally. METHODS: The study recruits patients diagnosed with a variety of psychiatric disorders and has a longitudinal cohort design with an assessment at baseline and at one-year follow-up. The primary outcome measure is cognitive functioning. The secondary outcome measures include clinical symptoms, electroencephalographic, genetic and blood markers (e.g., fatty acids), and hair cortisol concentration levels. DISCUSSION: The Across study provides an opportunity for a transdiagnostic, bottom-up, data-driven approach of investigating cognition in relation to symptoms and biological parameters longitudinally in patients with psychiatric disorders. The study may help to find new clusters of symptoms, biological markers, and cognitive dysfunctions that have better prognostic value than the current diagnostic categories. Furthermore, increased insight into the relationship among cognitive deficits, biological parameters, and psychiatric symptoms can lead to new treatment possibilities. TRIAL REGISTRATION: Netherlands Trial Register (NTR): NL8170.

Opening the Black Box of Cognitive-Behavioural Case Management in Clients with Ultra-High Risk for Psychosis.

BACKGROUND: Cognitive-behavioural therapy (CBT) is the first-choice treatment in clients with ultra-high risk (UHR) for psychosis. However, CBT is an umbrella term for a plethora of different strategies, and little is known about the association between the intensity and content of CBT and the severity of symptomatic outcome. METHODS: A sample of 268 UHR participants received 6 months of CBT with case management (CBCM) in the context of the multi-centre NEURAPRO trial with monthly assessments of attenuated psychotic symptoms (APS). Using multilevel regressions and controlling for the initial severity of APS, the associations between (1) number of CBCM sessions received and severity of APS and (2) specific CBCM components and severity of APS were investigated. RESULTS: In month 1, a higher number of sessions and more assessment of symptoms predicted an increase in APS, while in month 3, a higher number of sessions and more monitoring predicted a decrease in the level of APS. More therapeutic focus on APS predicted an overall increase in APS. CONCLUSIONS: Our findings indicate that the association between intensity/content of CBCM and severity of APS in a sample of UHR participants depends on the length of time in treatment. CBCM may positively impact the severity of APS later in the course of treatment. Therefore, it would seem important to keep UHR young people engaged in treatment beyond this initial period. Regarding the specific content of CBCM, a therapeutic focus on APS may not necessarily be beneficial in reducing the severity of APS, a possibility in need of further investigation.

Cognitive effects of deep brain stimulation in patients with obsessive-compulsive disorder.

BACKGROUND: Deep brain stimulation (DBS) is a promising treatment for treatment-refractory obsessive-compulsive disorder (OCD). However, the effects of DBS on cognitive functioning remain unclear. Therefore, we aimed to assess cognitive safety of DBS for treatment-refractory OCD and the association between clinical changes and cognitive functioning. METHODS: Patients with treatment-refractory OCD treated with DBS targeted at the nucleus accumbens (NAcc) were compared with a control group of 14 patients with treatment-refractory OCD treated with care as usual. We assessed cognitive functioning at baseline, 3 weeks postoperatively and following 8 months of DBS. We compared change in clinical symptoms with cognitive changes. RESULTS: There were 16 patients in the DBS group and 14 patients in the control group. Three weeks postoperatively, the DBS group showed a significantly reduced performance on measures of visual organization and verbal fluency and a trend toward reduced performance on measures of visual memory and abstract reasoning. Cognitive functioning was found to be stable on all other measures. After 8 months of DBS, reduced performances persisted, except for a significant improvement in verbal fluency. Cognitive functioning in all other domains remained unaffected. We found no correlation between improvement of clinical symptoms and cognitive changes. LIMITATIONS: A limitation of this study was its relatively small sample size. CONCLUSION: Deep brain stimulation targeted at the NAcc may be considered a safe method in terms of cognition because cognitive functioning was unaffected on most neuropsychological measures. Nevertheless, we observed some minor reduced performance on specific measures of executive functioning that were possibly associated with surgical intervention. Our results suggest that severity of OCD symptoms is independent of cognitive functioning.

The distribution of self-reported psychotic-like experiences in non-psychotic help-seeking mental health patients in the general population; a factor mixture analysis.

PURPOSE: Factor mixture analysis (FMA) and item response mixture models in the general population have shown that the psychosis phenotype has four classes. This study attempted to replicate this finding in help-seeking people accessing mental health services for symptoms of non-psychotic mental disorders. METHODS: All patients (18-35 years old) referred for non-psychotic mental health problems to the secondary mental healthcare service in The Hague between February 2008 to February 2010 (N = 3,694), were included. Patients completed the Prodromal Questionnaire (PQ). Hybrid latent class analysis was applied to explore the number, size and symptom profiles of the classes. RESULTS: The FMA resulted in four classes. Class 1 (N = 1,039, 28.1%) scored high on conceptual disorganization, inattention and mood disorder. Patients in Class 2 (N = 619, 16.8%) endorsed almost all PQ-items, were more often screened as being psychotic or at high risk of developing psychosis, without care takers noticing. In Class 3 (N = 1,747, 47.3%) perplexity, paranoia and negative symptoms were more prevalent. Patients were more often at high risk of developing psychosis. Class 4 (N = 286, 7.7%) represented the 'normative' group with low probabilities for all items. DISCUSSION: The results support the hypothesis that a representation in four classes of psychotic-like experiences can also be applied in a help-seeking population.

Corrigendum: Usability, feasibility, and effect of a biocueing intervention in addition to a moderated digital social therapy-platform in young people with emerging mental health problems: a mixed-method approach.

[This corrects the article DOI: 10.3389/fpsyt.2022.871813.].

Transdiagnostic Ecological Momentary Intervention for Improving Self-Esteem in Youth Exposed to Childhood Adversity: The SELFIE Randomized Clinical Trial.

Importance: Targeting low self-esteem in youth exposed to childhood adversity is a promising strategy for preventing adult mental disorders. Ecological momentary interventions (EMIs) allow for the delivery of youth-friendly, adaptive interventions for improving self-esteem, but robust trial-based evidence is pending. Objective: To examine the efficacy of SELFIE, a novel transdiagnostic, blended EMI for improving self-esteem plus care as usual (CAU) compared with CAU only. Design, Setting, and Participants: This was a 2-arm, parallel-group, assessor-blinded, randomized clinical trial conducted from December 2018 to December 2022. The study took place at Dutch secondary mental health services and within the general population and included youth (aged 12-26 years) with low self-esteem (Rosenberg Self-Esteem Scale [RSES] <26) exposed to childhood adversity. Interventions: A novel blended EMI (3 face-to-face sessions, email contacts, app-based, adaptive EMI) plus CAU or CAU only. Main Outcomes and Measures: The primary outcome was RSES self-esteem at postintervention and 6-month follow-up. Secondary outcomes included positive and negative self-esteem, schematic self-beliefs, momentary self-esteem and affect, general psychopathology, quality of life, observer-rated symptoms, and functioning. Results: A total of 174 participants (mean [SD] age, 20.7 [3.1] years; 154 female [89%]) were included in the intention-to-treat sample, who were primarily exposed to childhood emotional abuse or neglect, verbal or indirect bullying, and/or parental conflict. At postintervention, 153 participants (87.9%) and, at follow-up, 140 participants (80.5%), provided primary outcome data. RSES self-esteem was, on average, higher in the experimental condition (blended EMI + CAU) than in the control condition (CAU) across both postintervention and follow-up as a primary outcome (B = 2.32; 95% CI, 1.14-3.50; P < .001; Cohen d-type effect size [hereafter, Cohen d] = 0.54). Small to moderate effect sizes were observed suggestive of beneficial effects on positive (B = 3.85; 95% CI, 1.83-5.88; P < .001; Cohen d = 0.53) and negative (B = -3.78; 95% CI, -6.59 to -0.98; P = .008; Cohen d = -0.38) self-esteem, positive (B = 1.58; 95% CI, 0.41-2.75; P = .008; Cohen d = 0.38) and negative (B = -1.71; 95% CI, -2.93 to -0.48; P = .006; Cohen d = -0.39) schematic self-beliefs, momentary self-esteem (B = 0.29; 95% CI, 0.01-0.57; P = .04; Cohen d = 0.24), momentary positive affect (B = 0.23; 95% CI, 0.01-0.45; P = .04; Cohen d = 0.20), momentary negative affect (B = -0.33; 95% CI, -0.59 to -0.03, P = .01, Cohen d = -0.27), general psychopathology (B = -17.62; 95% CI, -33.03 to -2.21; P = .03; Cohen d = -0.34), and quality of life (B = 1.16; 95% CI, 0.18-2.13; P = .02; Cohen d = 0.33) across postintervention and follow-up. No beneficial effects on symptoms and functioning were observed. Conclusions and Relevance: A transdiagnostic, blended EMI demonstrated efficacy on the primary outcome of self-esteem and signaled beneficial effects on several secondary outcomes. Further work should focus on implementing this novel EMI in routine public mental health provision. Trial Registration: Dutch Trial Register Identifier:NL7129(NTR7475).

Proteomic Biomarkers for the Prediction of Transition to Psychosis in Individuals at Clinical High Risk: A Multi-cohort Model Development Study.

Psychosis risk prediction is one of the leading challenges in psychiatry. Previous investigations have suggested that plasma proteomic data may be useful in accurately predicting transition to psychosis in individuals at clinical high risk (CHR). We hypothesized that an a priori-specified proteomic prediction model would have strong predictive accuracy for psychosis risk and aimed to replicate longitudinal associations between plasma proteins and transition to psychosis. This study used plasma samples from participants in 3 CHR cohorts: the North American Prodrome Longitudinal Studies 2 and 3, and the NEURAPRO randomized control trial (total n = 754). Plasma proteomic data were quantified using mass spectrometry. The primary outcome was transition to psychosis over the study follow-up period. Logistic regression models were internally validated, and optimism-corrected performance metrics derived with a bootstrap procedure. In the overall sample of CHR participants (age: 18.5, SD: 3.9; 51.9% male), 20.4% (n = 154) developed psychosis within 4.4 years. The a priori-specified model showed poor risk-prediction accuracy for the development of psychosis (C-statistic: 0.51 [95% CI: 0.50, 0.59], calibration slope: 0.45). At a group level, Complement C8B, C4B, C5, and leucine-rich α-2 glycoprotein 1 (LRG1) were associated with transition to psychosis but did not surpass correction for multiple comparisons. This study did not confirm the findings from a previous proteomic prediction model of transition from CHR to psychosis. Certain complement proteins may be weakly associated with transition at a group level. Previous findings, derived from small samples, should be interpreted with caution.

Is a schizo-obsessive subtype associated with cognitive impairment? Results from a large cross-sectional study in patients with psychosis and their unaffected relatives.

The current study investigated whether candidate cognitive endophenotypes may be used to validate a schizo-obsessive subtype. Using within-subject random effect regression analyses and cross-trait cross-relative analyses, we evaluated the association between obsessive-compulsive symptoms (OCSs) and cognitive performance in 984 patients with nonaffective psychosis (22.5% with OCSs), 973 unaffected siblings (7.7% with OCSs), 851 parents (4.2% with OCSs), and 573 controls (4.5% with OCSs). No significant within-subject associations between OCSs and cognitive functioning were found for patients and siblings. Severity of OCSs was associated with worse set-shifting ability in parents and worse processing speed in controls, but effect sizes were small (0.10 and 0.05 respectively). Cross-trait cross-relative analyses yielded no significant results. Contrary to our expectations, neither within-subject analyses nor cross-relative analyses yielded a clear association between OCSs and cognitive performance. Results do not support a schizo-obsessive subtype associated with cognitive impairment.

Psychosocial outcome in patients at clinical high risk of psychosis: a prospective follow-up.

PURPOSE: In patients at clinical high risk (CHR) of psychosis, transition to psychosis has been the focus of recent studies. Their broader outcome has received less attention. We studied psychosocial state and outcome in CHR patients. METHODS: In the European Prediction of Psychosis Study, 244 young help-seeking CHR patients were assessed with the Strauss and Carpenter Prognostic Scale (SCPS) at baseline, and 149 (61.1%) of them were assessed for the second time at the 18-month follow-up. The followed patients were classified into poor and good outcome groups. RESULTS: Female gender, ever-married/cohabitating relationship, and good working/studying situation were associated with good baseline SCPS scores. During follow-up, patients' SCPS scores improved significantly. Good follow-up SCPS scores were predicted by higher level of education, good working/studying status at baseline, and white ethnicity. One-third of the followed CHR patients had poor global outcome. Poor working/studying situation and lower level of education were associated with poor global outcome. Transition to psychosis was associated with baseline, but not with follow-up SCPS scores or with global outcome. CONCLUSION: The majority of CHR patients experience good short-term recovery, but one-third have poor psychosocial outcome. Good working situation is the major indicator of good outcome, while low level of education and non-white ethnicity seem to be associated with poor outcome. Transition to psychosis has little effect on psychosocial outcome in CHR patients. In treating CHR patients, clinicians should focus their attention on a broader outcome, and not only on preventing transition to psychosis.

The Effects of a Digital, Transdiagnostic, Clinically and Peer-Moderated Treatment Platform for Young People With Emerging Mental Health Complaints: Repeated Measures Within-Subjects Study.

BACKGROUND: To address the growing prevalence of youth mental health problems, early intervention is crucial to minimize individual, societal, and economic impacts. Indicative prevention aims to target emerging mental health complaints before the onset of a full-blown disorder. When intervening at this early stage, individuals are more responsive to treatment, resulting in cost-effective outcomes. The Moderated Online Social Therapy platform, which was successfully implemented and proven effective in Australia, is a digital, peer- and clinically moderated treatment platform designed for young people. The Netherlands was the first country outside Australia to implement this platform, under the name Engage Young People Early (ENYOY). It has the potential to reduce the likelihood of young people developing serious mental health disorders. OBJECTIVE: This study aims to investigate the effects on young people using the ENYOY-platform in relation to psychological distress, psychosocial functioning, and positive health parameters. METHODS: Dutch-speaking young people with emerging mental health complaints (N=131) participated in the ENYOY-platform for 6 months in a repeated measures within-subjects study. Psychological distress, psychosocial functioning, and positive health parameters were assessed at baseline and 3, 6, and 12 months. Repeated measures ANOVA was conducted and adjusted for age, sex, therapy, and community activity. The Reliable Change Index and Clinically Significant Index were computed to compare the baseline with the 6- and 12-month measurements. The missing data rate was 22.54% and the dropout rate 62.6% (82/131). RESULTS: The primary analysis (77/131, 58.8%) showed that psychological distress decreased and psychosocial functioning improved over time with large effect sizes (P<.001 in both cases; ηp2=0.239 and 0.318, respectively) independent of age (P=.76 for psychological distress and P=.48 for psychosocial functioning), sex (P=.24 and P=.88, respectively), therapy activity (P=.49 and P=.80, respectively), or community activity (P=.59 and P=.48, respectively). Similarly, secondary analyses (51/131, 38.9%) showed significant effects of time on the quality of life, well-being, and meaningfulness positive health parameters (P<.05; ηp2=0.062, 0.140, and 0.121, respectively). Improvements in all outcome measures were found between baseline and 3 and 6 months (P≤.001-.01; d=0.23-0.62) and sustained at follow-up (P=.18-.97; d=0.01-0.16). The Reliable Change Index indicated psychological distress improvements in 38% (39/102) of cases, no change in 54.9% (56/102) of cases, and worsening in 5.9% (6/102) of cases. Regarding psychosocial functioning, the percentages were 50% (51/102), 43.1% (44/102), and 6.9% (7/102), respectively. The Clinically Significant Index demonstrated clinically significant changes in 75.5% (77/102) of cases for distress and 89.2% (91/102) for functioning. CONCLUSIONS: This trial demonstrated that the ENYOY-platform holds promise as a transdiagnostic intervention for addressing emerging mental health complaints among young people in the Netherlands and laid the groundwork for further clinical research. It would be of great relevance to expand the population on and service delivery of the platform. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1186/s12888-021-03315-x.

Usability, Feasibility, and Effect of a Biocueing Intervention in Addition to a Moderated Digital Social Therapy-Platform in Young People With Emerging Mental Health Problems: A Mixed-Method Approach.

Introduction: To optimize treatment, it is of utmost importance to take into account the myriad of biological, social, and psychological changes that young people go through during adolescence which make them more vulnerable for developing mental health problems. Biocueing, a non-invasive method to transform physiological parameters into an observable signal, could strengthen stress- and emotion regulation by cueing physiologically unusual values in daily life. The aim of this study is to investigate the usability, feasibility, and exploratory effect of biocueing in addition to ENgage YOung people earlY (ENYOY), a moderated digital social therapy-platform, in young people with emerging mental health complaints. Methods: A user-centered mixed-method design was used. A focus group was conducted to optimize the ENYOY-platform and biocueing intervention. Biocueing was operationalized by a smartwatch and the Sense-IT app. A within-subjects design was used; 10 days for all participants 'biofeedback off' (control), followed by 10 days 'biofeedback on' (experimental). Emotional awareness and perceived stress were measured using ecological momentary assessment. Eight individuals participated. User-friendliness, usability, and acceptance were assessed using a qualitative design. Results: Findings from the focus group resulted in several adaptations of the biocueing intervention to the ENYOY-platform and vice versa. The average measurement compliance rate was 78.8%. Level-one findings showed different individual effects on perceived stress and emotional awareness. Level-two analyses showed no overall effects on perceived stress (B = -0.020, p = 0.562) and overall positive effects on emotional awareness (B = 0.030, p = 0.048) with small effect sizes (Improvement Rate Difference = 0.05-0.35). The intervention was found to be acceptable and showed moderate usability. Participants indicated they experienced improvements in reflection on feelings and changes in behavior, such as pausing and evaluating the situation. Conclusion: These preliminary results show that biocueing could be a promising addition to digital treatment platforms and help young people become more emotionally aware. Improvements should be made regarding the usability and acceptability of the smartwatch, as well as more extensive integration of the biocueing intervention with a digital treatment platform. It would be relevant to gain a better understanding of which individuals would benefit most from an additional biocueing intervention.

The interplay between psychopathological symptoms: transdiagnostic cross-lagged panel network model.

BACKGROUND: Recent paradigm shifts suggest that psychopathology manifests through dynamic interactions between individual symptoms. AIMS: To investigate the longitudinal relationships between symptoms in a transdiagnostic sample of patients with psychiatric disorders. METHOD: A two-wave, cross-lagged panel network model of 15 nodes representing symptoms of depression, (social) anxiety and attenuated psychotic symptoms was estimated, using baseline and 1-year follow-up data of 222 individuals with psychiatric disorders. Centrality indices were calculated to determine important predictors and outcomes. RESULTS: Our results demonstrated that the strongest relationships in the network were between (a) more suicidal ideation predicting more negative self-view, and (b) autoregressive relationships of social anxiety symptoms positively reinforcing themselves. Negative self-view was the most predictable node in the network as it had the highest 'in-expected influence' centrality, and may be an important transdiagnostic outcome symptom. CONCLUSIONS: The results give insight into longitudinal interactions between symptoms, which interact in ways that do not adhere to broader diagnostic categories. Our results suggest that self-view can also be a transdiagnostic outcome of psychopathology rather than just a predictor, as is normally posited, and may especially have an important relationship with suicidal ideation. Overall, our study demonstrates the dynamic complexity of psychopathology, and further supports the importance of investigating symptom interactions of different psychopathological dimensions over time and across disorders.

Moderated digital social therapy for young people with emerging mental health problems: A user-centered mixed-method design and usability study.

Introduction: Over 25% of Dutch young people are psychologically unhealthy. Individual and societal consequences that follow from having mental health complaints at this age are substantial. Young people need care which is often unavailable. ENgage YOung people earlY (ENYOY) is a moderated digital social therapy-platform that aims to help youngsters with emerging mental health complaints. Comprehensive research is being conducted into the effects and to optimize and implement the ENYOY-platform throughout the Netherlands. The aim of this study is to explore the usability and user experience of the ENYOY-platform. Methods: A user-centered mixed-method design was chosen. 26 young people aged 16-25 with emerging mental health complaints participated. Semi-structured interviews were conducted to explore usability, user-friendliness, impact, accessibility, inclusivity, and connection (Phase 1). Phase 2 assessed usability problems using the concurrent and retrospective Think Aloud-method. User experience and perceived helpfulness were assessed using a 10-point rating scale and semi-structured interviews (Phase 3). The Health Information Technology Usability Evaluation Scale (Health-ITUES; Phase 1) and System Usability Scale (SUS; Phase 2 and 3) were administered. Qualitative data was analyzed using thematic analysis. Task completion rate and time were tracked and usability problems were categorized using the Nielsen's rating scale (Phase 2). Results: Adequate to high usability was found (Phase 1 Health-ITUES 4.0(0.34); Phase 2 SUS 69,5(13,70); Phase 3 SUS 71,6(5,63)). Findings from Phase 1 (N = 10) indicated that users viewed ENYOY as a user-friendly, safe, accessible, and inclusive initiative which helped them reduce their mental health complaints and improve quality of life. Phase 2 (N = 10) uncovered 18 usability problems of which 5 of major severity (e.g. troubles accessing the platform). Findings from Phase 3 (N = 6) suggested that users perceived the coaching calls the most helpful [9(0.71)] followed by the therapy content [6.25(1.41)]. Users liked the social networking aspect but rated it least helpful [6(2.1)] due to inactivity. Conclusion: The ENYOY-platform has been found to have adequate to high usability and positive user experiences were reported. All findings will be transferred to the developmental team to improve the platform. Other evaluation methods and paring these with quantitative outcomes could provide additional insight in future research.

Effects of omega-3 polyunsaturated fatty acid supplementation on cognitive functioning in youth at ultra-high risk for psychosis: secondary analysis of the NEURAPRO randomised controlled trial.

BACKGROUND: Cognitive impairments are well-established features of psychotic disorders and are present when individuals are at ultra-high risk for psychosis. However, few interventions target cognitive functioning in this population. AIMS: To investigate whether omega-3 polyunsaturated fatty acid (n-3 PUFA) supplementation improves cognitive functioning among individuals at ultra-high risk for psychosis. METHOD: Data (N = 225) from an international, multi-site, randomised controlled trial (NEURAPRO) were analysed. Participants were given omega-3 supplementation (eicosapentaenoic acid and docosahexaenoic acid) or placebo over 6 months. Cognitive functioning was assessed with the Brief Assessment of Cognition in Schizophrenia (BACS). Mixed two-way analyses of variance were computed to compare the change in cognitive performance between omega-3 supplementation and placebo over 6 months. An additional biomarker analysis explored whether change in erythrocyte n-3 PUFA levels predicted change in cognitive performance. RESULTS: The placebo group showed a modest greater improvement over time than the omega-3 supplementation group for motor speed (ηp2 = 0.09) and BACS composite score (ηp2 = 0.21). After repeating the analyses without individuals who transitioned, motor speed was no longer significant (ηp2 = 0.02), but the composite score remained significant (ηp2 = 0.02). Change in erythrocyte n-3 PUFA levels did not predict change in cognitive performance over 6 months. CONCLUSIONS: We found no evidence to support the use of omega-3 supplementation to improve cognitive functioning in ultra-high risk individuals. The biomarker analysis suggests that this finding is unlikely to be attributed to poor adherence or consumption of non-trial n-3 PUFAs.

Evidence that complement and coagulation proteins are mediating the clinical response to omega-3 fatty acids: A mass spectrometry-based investigation in subjects at clinical high-risk for psychosis.

Preliminary evidence indicates beneficial effects of omega-3 polyunsaturated fatty acids (PUFAs) in early psychosis. The present study investigates the molecular mechanism of omega-3 PUFA-associated therapeutic effects in clinical high-risk (CHR) participants. Plasma samples of 126 CHR psychosis participants at baseline and 6-months follow-up were included. Plasma protein levels were quantified using mass spectrometry and erythrocyte omega-3 PUFA levels were quantified using gas chromatography. We examined the relationship between change in polyunsaturated PUFAs (between baseline and 6-month follow-up) and follow-up plasma proteins. Using mediation analysis, we investigated whether plasma proteins mediated the relationship between change in omega-3 PUFAs and clinical outcomes. A 6-months change in omega-3 PUFAs was associated with 24 plasma proteins at follow-up. Pathway analysis revealed the complement and coagulation pathway as the main biological pathway to be associated with change in omega-3 PUFAs. Moreover, complement and coagulation pathway proteins significantly mediated the relationship between change in omega-3 PUFAs and clinical outcome at follow-up. The inflammatory protein complement C5 and protein S100A9 negatively mediated the relationship between change in omega-3 PUFAs and positive symptom severity, while C5 positively mediated the relationship between change in omega-3 and functional outcome. The relationship between change in omega-3 PUFAs and cognition was positively mediated through coagulation factor V and complement protein C1QB. Our findings provide evidence for a longitudinal association of omega-3 PUFAs with complement and coagulation protein changes in the blood. Further, the results suggest that an increase in omega-3 PUFAs decreases symptom severity and improves cognition in the CHR state through modulating effects of complement and coagulation proteins.

Semantic fluency deficits and reduced grey matter before transition to psychosis: a voxelwise correlational analysis.

Early identification of subjects with an increased risk of psychosis is necessary to develop interventions to delay or prevent disease onset. We recently reported that decreased semantic verbal fluency performance in ultra high risk (UHR) subjects predicts the development of psychosis (Becker et al., 2010). The present study investigated whether semantic and verbal fluency scores correlate with grey matter density in UHR subjects. Thirty-seven UHR subjects underwent structural MRI scanning and verbal fluency assessment after which they were followed up for 2 years. Using voxel-based morphometry, we investigated whether grey matter density correlated with verbal fluency scores in 10 UHR subjects who developed psychosis during follow-up and 27 UHR subjects who did not develop psychosis. In UHR subjects developing psychosis, lower semantic fluency scores correlated significantly with reduced grey matter density in the right superior and middle temporal gyrus, the right insula, and the left anterior cingulate cortex. This study shows that a correlation between semantic fluency performance and grey matter density in task-related areas can differentiate between UHR subjects who subsequently will develop psychosis and those who will not. Combining these two measures could improve psychosis prediction in UHR subjects.