Low self-esteem is an important and potentially modifiable risk factor for the development and outcome of psychotic disorders. The factors involved in low self-esteem in psychotic disorders are not yet fully understood. The current study aims to investigate the cross-sectional and longitudinal associations between (changes in) self-esteem and severity of psychotic symptoms, internalized stigma, negative reaction to antipsychotics, personal recovery, childhood bullying, childhood trauma, and social support in symptomatically remitted first-episode psychosis (FEP) patients.

Data from the ongoing longitudinal Handling Antipsychotic Medication: Long-term Evaluation of Targeted Treatment study were used. Participants were in symptomatic remission for 3–6 months after the FEP. Cross-sectional associations (N = 299) were investigated through Pearson’s correlations, and longitudinal changes (N = 238) were investigated via linear regressions with inverse probability weighting.

Cross-sectionally, we found that lower self-esteem was related to higher severity of symptoms, higher internalized stigma, higher childhood trauma (specifically emotional neglect), higher childhood bullying, more negative side effects of antipsychotic medication, lower personal recovery, and lower social support. Longitudinally, contrary to our hypothesis, we found that higher baseline internalized stigma, higher childhood trauma (specifically emotional abuse), and a higher baseline negative subjective reaction to antipsychotics predicted an increase in self-esteem after 6 months. Furthermore, a decrease in psychotic symptoms, internalized stigma, and negative subjective reaction to antipsychotics, and an increase in social support predicted an increase in self-esteem.

Early intervention programs for psychotic disorders should target factors related to changes in self-esteem. This might improve self-esteem and thereby promote recovery.

Spatial neglect is a heterogeneous post-stroke disorder with subtypes differing in reference frames, processing stages, and spatial domains. While egocentric peri-personal neglect recovery has been studied, recovery trajectories of allocentric peri-personal visuospatial and personal neglect remain unclear. This study investigated recovery time courses of egocentric and allocentric peri-personal visuospatial and personal neglect during the first 12 weeks post-stroke; whether initial severity predicts recovery and defines distinct patient clusters; and how subtypes interrelate over time.

Forty-one first-ever stroke patients were evaluated at weeks 3, 5, 8, and 12 post-stroke using the Broken Hearts Test, Line Bisection Test, Visuospatial Search Time Test, and Fluff Test. Recovery was analyzed using linear mixed models, clustering with Gaussian finite mixture models, and interrelationships using Spearman correlations.

Significant improvements occurred in egocentric and allocentric peri-personal visuospatial and personal neglect, primarily between weeks 3 and 5, followed by a plateau. The Line Bisection Test detected no changes. Higher initial severity predicted greater residual impairment. Cluster analysis identified near-normal, mild, and moderate-to-severe baseline subgroups with distinct recovery trajectories. Moderate-to-good correlations (ρ = 0.33 – 0.55) emerged between egocentric and allocentric neglect at week 3 and when timepoints were pooled.

Neglect improved mainly between weeks 3 and 5 after which recovery plateaued, mirroring motor and language recovery and suggesting a shared time-limited window. Initial severity was a determinant of recovery, highlighting the value of early severity stratification to monitor and support recovery potential after stroke. As subtypes are distinctive, assessment should include multiple neglect tests.

Since 2019 the Dutch National Healthcare Institute has operated a coverage with evidence development (CED) program for specific products with insufficient evidence of their clinical benefit: orphan medicinal products (OMPs), medicines with conditional marketing authorization (CMA), and medicines with marketing authorization under exceptional circumstances (AEC). The objective of this study is to give an overview of this program and reflect on learnings, challenges, and opportunities.

This study is a narrative policy review of the Dutch CED program and describes the different phases and stakeholder involvement. Additionally, an overview of the medicines included in the CED program is presented and put in an international perspective.

The CED program consists of four phases: candidate prescreening, research protocol drafting, signing of process agreement and financial agreement, and controlled access. Stakeholders are involved intensively throughout the process. Since 2019, six medicines have entered the program. The program is used to fill different evidence gaps for various types of medicines and indications. In other countries, these medicines are often included in restricted reimbursement programs.

The CED program is gathering clinical effectiveness data while providing patient access to OMPs, CMA, and AEC products. Important facilitating factors for the program were identified, including the involvement of all stakeholders, the only-in-research approach of data gathering, and the case-by-case evidence generation requirements and duration. Continuous evaluation is needed as the program does not yet include the expected number of medicines, and no conclusion can be drawn so far on the usefulness of the data collection.

Evidence on psychological side effects (PSEs) of antipsychotic medication after remission from first-episode psychosis (FEP), and their momentary impact on daily life, is limited. This study examined how Dopamine-2 (D2) affinity and antipsychotic dosage relate to momentary PSEs.

This ecological momentary assessment (EMA) study included baseline data from 56 participants in the ongoing Handling Antipsychotic Medication: Long-term Evaluation of Targeted Treatment (HAMLETT) trial. Momentary mental states indicative of reduced affect intensity, stability, and variability, as well as avolition and mental fatigue, were assessed 10×/day for eight days (N = 3,005 data points). Since these PSEs may result from D2-receptor actions, antipsychotics were classified by receptor affinity and mechanism of action. Multilevel mixed-effects regression models examined serial cross-sectional associations between D2 affinity or dosage and concurrent PSEs, both overall and separately for mornings, daytimes, and evenings.

Higher antipsychotic dosages were associated with reduced affect variability (Beta [B] = −1.40 [95% confidence interval [CI]: −2.52; −0.29]) and decreased positive affect stability (B = 0.23 [95% CI: 0.04; 0.42]) and intensity (B = −1.11 [95% CI: −1.97; −0.24]). The latter was also associated with the use of high-affinity D2 antagonists versus partial D2 agonists (B = 12.98 [95% CI: 2.43; 23.53]) and versus low-affinity D2 antagonists (B = 10.04 [95% CI: 0.59; 19.49]). Other PSEs were not associated with D2 affinity/dosage. Results were relatively consistent across daytimes.

Higher antipsychotic dosage and high-affinity D2 antagonists were associated with decreased positive affect after remission from FEP, which may partly drive the frequently reported blunting of emotional experience.

After remission of a first-episode psychosis (FEP), antipsychotic discontinuation is associated with an increased risk of relapse compared to maintenance treatment. We studied short and longer-term effects of discontinuation of D2 receptor (D2R) antagonist and partial agonist antipsychotics on striatal dopamine D2/3R availability in FEP patients.

Remitted FEP patients underwent two [11C]raclopride PET scans to measure striatal D2/3R availability: 1 week after antipsychotic discontinuation (n = 16 antagonist users, n = 6 partial agonist users) and after being medication free for 6–8 weeks (n = 8 antagonist users, n = 5 partial agonist users). Fifteen matched healthy controls were scanned once. Psychotic relapse was monitored up to 12 months after discontinuation.

One week after discontinuation, D2R antagonist discontinuers showed higher striatal binding potential (BPND) than partial D2R agonist discontinuers (p < 0.001, CI = 0.749 to 1.681) and controls (p = 0.045, CI = 0.008 to 0.708), while partial agonist discontinuers had significantly lower BPND than controls (p = 0.001, CI = -1.326 to -0.386). 6-8 weeks after discontinuation, former antagonist users showed similar BPND to controls (p > 0.25), whereas former partial agonist users had higher BPND than controls (p = 0.027, CI = 0.069 to 1.085). Participants who discontinued antagonists relapsed more often (81%) than those who discontinued partial agonists (17%)(χ2 = 5.32, p = 0.021).

Discontinuation of partial D2R agonists may affect D2/3R availability differently than discontinuation of antagonists, which might explain the greater relapse risk after tapering antagonists than partial agonist antipsychotics.

Virtual reality (VR) may improve psychological treatments for psychotic disorders. We investigated the effects of VR-based cognitive behavior therapy for paranoid ideation (VR-CBTp) compared to standard CBTp.

We conducted a pragmatic, single-blind, randomized clinical trial in seven mental health centers across the Netherlands and Belgium. A total of 98 participants with a psychotic spectrum disorder and paranoid ideation were randomized to a maximum of 16 sessions of VR-CBTp (n = 48) or CBTp (n = 50). The primary outcome was momentary paranoia, measured with the experience sampling method (ESM) at posttreatment. Secondary measures, assessed at baseline, posttreatment, and 3-month follow-up, included symptoms (paranoia, hallucination, depression, cognition, and anxiety related), social functioning, self-esteem, and schemes.

Both groups showed reductions in momentary paranoia between baseline and posttreatment (n = 56, b = −15.0, effect size [ES] = 0.65), but those were greater for VR-CBT (interaction b = 8.3, ES = 0.62). Reductions remained at follow-up (n = 50, b = −10.7, ES = 0.57) but not the interaction. Limited ESM compliance resulted in data loss; however, secondary paranoia measures did confirm improvements (ES range = 0.66–1.15, n = 78–81), but not the interaction. Both groups improved in symptoms, self-esteem, and social functioning. Interaction effects in favor of VR-CBTp were found for safety behavior, depression, and self-esteem at posttreatment, and self-esteem and anxiety at follow-up. For VR-CBTp, 37.5% did not complete treatment; for CBTp, this was 24.0%. Completers, on average, received 12.7 (VR-CBTp: standard deviation [SD] = 3.9) and 15.1 (CBTp: SD = 2.5) sessions.

Both CBTp and VR-CBTp are efficacious treatments for paranoid ideation, but VR-CBTp may be somewhat more effective. Limitations concern missing primary outcome data and a lower sample size than anticipated.

Cognitive Behavioural Therapy for psychosis (CBTp) is an effective psychological treatment for Schizophrenia Spectrum and other psychotic Disorders (SSD). Despite guidelines recommending CBTp for all psychotic disorder patients, many SSD patients lack access to the treatment and little is known about its long-term cost-effectiveness. The aim of this study is to evaluate the cost-effectiveness of CBTp for the treatment of psychotic disorders through scenario analysis from a healthcare perspective.

Increased implementation of CBTp was evaluated using a real-world SSD population (N = 12,835) from the northern Netherlands (2010–2019). A patient-level model was used to simulate the long-term effects of rehospitalisation rate. We compared treatment as usual (TAU) with the same TAU plus hypothetical CBTp for all individuals not having received such in TAU, hence patients who received any CBTp sessions prior were excluded (N = 2,679). Outcomes considered were quality-adjusted life years gained and total costs of mental healthcare. Additional sensitivity and scenario analyses were performed to evaluate structural and parameter uncertainty.

TAU+CBTp was a cost-effective treatment in 61.2% of the simulations. The simulated net present values for QALY gains were 0.038, and for incremental costs were €492 per patient on average, resulting in an expected incremental cost-effectiveness ratio (ICER) of €12,947.

The evaluation shows that CBTp is likely a cost-effective treatment, although results were uncertain. These findings stress the importance of sufficient availability of CBTp for SSD patients. Making CBTp available for all eligible SSD patients may lead to substantial health gains for the SSD population and cost savings from the healthcare perspective in The Netherlands.

Insight in nonverbal correlates of paranoid ideation can potentially help improve diagnostic procedures and guide interventions. The aim was to systematically evaluate the scientific evidence investigating nonverbal correlates of paranoid ideation.

The review follows the PRISMA guidelines. Databases PsycINFO, PubMed, Web of Science, and Cinahl were searched for studies concerning the use of standardized instruments for both verbal and nonverbal measurements of paranoid ideation in adult participants. Quality of studies was evaluated using the Effective Public Health Practice Project tool. Data were systematically extracted and summarized thematically and narratively. This review was registered with PROSPERO (CRD42022288001).

The search strategy yielded 3962 results of which 22 papers met inclusion criteria. Half (n = 11) of the included articles included patients with a diagnosis on the psychosis spectrum, the other articles (n = 11) studied healthy populations. Identified nonverbal categories were spatial behavior (n = 6), brain region activity (n = 5), visual perception (n = 5), stress physiology (n = 4), information processing (n = 3), and aggression (n = 1). Some studies investigated multiple nonverbal categories.

Evidence was strongest for spatial behavior and brain region activity as nonverbal correlates of paranoid ideation. Evidence for stress physiology, information processing, and aggression as potential nonverbal correlates was less robust, due to inconsistent findings and small numbers of publications. Using nonverbal methods to assess paranoid ideation requires more investigation and evaluation. The integration of nonverbal assessments might offer new diagnostic possibilities that move beyond traditional verbal methods.

Young adults with a psychotic disorder often experience difficulties in social functioning. We developed a modular virtual reality treatment to improve social activities and participation by targeting common causes of social functioning difficulties in patients with a psychotic disorder (VR-SOAP). This paper details the development of this intervention, encompassing a piloting phase.

Using an iterative Scrum method with software engineers, clinicians, researchers, and individuals with lived experience of psychosis, we developed a treatment protocol along with a software prototype. Subsequently five patients with a psychotic disorder, aged 18–40, and three therapists, piloted VR-SOAP. Feasibility was assessed by means of interviews and session forms. Acceptability was evaluated along the seven domains of the Theoretical Framework of Acceptability (i.e. affective attitude, burden, ethicality, intervention coherence, opportunity costs, self-efficacy, and perceived effectiveness).

The final protocol consisted of the following modules and targets: 1. Motivation and Pleasure (negative symptoms); 2. Understanding Others (social cognition); 3. Safety and Trust (paranoid ideations and social anxiety); 4. Self-Image (self-esteem and self-stigma); 5. Communication (communication and interaction skills). Modules were piloted by the participating patients and therapists. The modules proved feasible and showed a high degree of acceptability on all seven domains of the acceptability framework.

The modular VR-SOAP treatment protocol and prototype was acceptable and feasible for therapists and patients. The primary recommendation for enhancement underscores the need for flexibility regarding the number of sessions and the content.

1. (1) Understanding the development and structure of a novel modular CBT treatment in VR.

2. (2) Learning to use specific VR modules to target negative symptoms, social cognition, paranoid ideations, social anxiety, self-esteem, and communication skills.

3. (3) Gaining insights into the feasibility and acceptability assessments of a novel modular CBT treatment in VR.

Real-world evidence (RWE) is increasingly used in healthcare research to address evidence gaps, reduce uncertainty about medical technology benefits, and provide real-world insights. Efforts to integrate RWE in regulatory and health technology assessment (HTA) processes are growing. However, variations among countries pose challenges. The objective is to analyze and compare various (inter)national RWE guidelines, focusing on real-world hospital data utilization.

We conducted a review to identify RWE guidance published from 2016 to 2023, with a focus on the EU5 nations (UK, France, Germany, Italy, and Spain) and the ONCOVALUE consortium affiliates (Finland, the Netherlands, Denmark, Italy, and Portugal). To ensure a comprehensive overview, we also investigated Canada, the European Medicines Agency (EMA), ISPOR, and the European Society for Medical Oncology (ESMO). We conducted in-depth interviews with HTA experts of all included countries, focusing on real-world hospital data within the European HTA context. The interviews underwent thematic analysis related to the utilization of RWE in HTA.

We identified nine guidance reports: six focused on HTA-RWE (Medicinrådet/Denmark, NICE/UK, AQuAS/Spain, HAS/France, IQWiG/Germany, CADTH/Canada), one from EMA, and two international (ISPOR, ESMO). Only NICE, IQWiG, and CADTH offered recommendations covering hospital data, emphasizing the data curation process. HAS addressed considerations in choosing secondary data sources, while IQWiG established robust criteria for registries to ensure data quality. Regarding patient-reported outcomes data, only HAS and NICE provided recommendations in their guidance. The HTA experts acknowledged the value of hospital data but expressed caution due to its unstructured nature, noting that the use of hospital-based RWE is more accepted in descriptive studies.

Guidances prioritize the clinical domain, emphasizing transparency, fitness for purpose, reproducibility, robustness, bias minimization, and generalizability. Notably, there’s a lack of comprehensive source-specific guidance for real-world data sources, including registries, hospitals, claims, and wearables. Enhanced guidance on the total data generation process, (data mapping, data federation), cost data, quality of life, and cross-border data usage would strengthen hospital-based RWE assessments.