Ditte Lammers Vernal

Schizophrenia and other primary psychotic disorders are severe mental disorders with major personal and societal impact. This review provides an overview of recent developments in the field of psychosis in Denmark, e.g., updated guidelines on diagnostics and treatment, expansion of early intervention services through increased funding, and treatment at different stages of psychosis. Lastly, selected emerging topics are briefly discussed: trauma-focused therapy, virtual reality-based interventions, and novel pharmacological treatments such as KarXT and glucagon-like peptide-1-based approaches.

Virtual reality (VR)-assisted avatar therapy has shown promising effects for reducing voice-related distress and overall severity of persistent auditory verbal hallucinations (AVH) in psychosis, yet the mechanisms underlying these improvements remain unclear. Emotional processes may play a role during therapeutic encounters with simulated voices, but it is unknown whether treatment effects involve broader changes in emotion regulation. We conducted secondary analyses of the CHALLENGE randomized clinical trial (N = 270), comparing a seven-session immersive VR-based avatar therapy with enhanced treatment as usual (standard care plus additional supportive counseling). Mediation models tested whether changes in cognitive reappraisal or expressive suppression, assessed using the Emotion Regulation Questionnaire (ERQ), mediated treatment effects on AVH severity and frequency at treatment end. Randomization to VR-assisted therapy did not significantly change ERQ reappraisal or suppression. Although higher reappraisal at follow-up was associated with lower AVH severity, no significant indirect effects were observed. These findings suggest that improvements following VR-assisted avatar therapy are unlikely to be explained by changes in self-reported trait emotion regulation strategies and may instead reflect more context-specific processes during voice confrontation.

Background: This exploratory study examined baseline characteristics modifying treatment effects on paranoia in individuals diagnosed with schizophrenia spectrum disorders following a 10-session virtual reality-based cognitive behavioral therapy for psychosis (VR-CBTp) or standard CBTp. Methods: All participants in the FaceYourFears trial were included ( n =254; CBTp n =128; VR-CBTp n =126). General linear and logistic regression models examined baseline variables associated with end-of-treatment paranoia. In covariate analyses, regression coefficients quantified associations across treatments. In moderation analyses, interaction terms (randomization x moderator) were tested, with corresponding regression coefficients estimated and assessed at the 25th (low), 50th (medium), and 75th (high) percentiles of continuous variables. Results: Across treatments, higher baseline avolition, safety behavior, delusion severity, and cognitive biases were associated with end-of-treatment paranoia. Moderation analyses revealed interactions for avolition, delusion severity, and negative other-beliefs. Although avolition and delusion severity were associated with poorer outcomes overall, individuals with high avolition and those with moderate-to-high delusion severity improved more in VR-CBTp than CBTp, whereas participants with lower delusion severity showed better outcomes in CBTp. No demographic (age, gender, education, and occupation) or other clinical characteristics (diagnosis, paranoia, social anxiety, depression, anhedonia, total negative symptoms, functioning, core beliefs, or interpersonal trauma) were significantly associated with outcome. Conclusions: This exploratory study generates hypotheses for future research, including VR-CBTp’s potential to engage individuals with high avolition. Given the modest effects and largely nonsignificant findings, both CBTp and VR-CBTp appear suitable for a wide range of individuals with paranoia, highlighting the importance of considering patient preferences.

Background: Auditory verbal hallucinations (voices) are common in schizophrenia spectrum disorders (SSD), and cause significant distress, making them a critical target in psychotherapeutic interventions. AVATAR therapy, conducted on a two-dimensional computer screen and its adaptation virtual reality-assisted therapy (VRT), using three-dimensional virtual reality (VR), have shown promise. Despite the potential of VRT, research exploring how specific VR characteristics can simulate voices experiences and affect therapy outcome remains scarce. Addressing this gap is key to refining VRT for persistent voices. Objective: This qualitative substudy of the CHALLENGE trial explored patient perspectives on modified VRT versions (VRT-Emotions, VRT-Environment, and VRT-Whiteboard) and their therapeutic impact, with the aim to inform intervention refinement and development. Methods: Semistructured interviews were conducted with 15 participants with SSD and persistent voices after undergoing the modified therapies. Data were analyzed within a pragmatist-critical realism orientation, with a hybrid deductive-inductive approach to thematic analysis. Reflexive team dialogues supported analytical rigor. Results: One overarching theme: A challenging yet transformative therapy, and three subthemes, corresponding to the specific modifications, were generated: Emotional connection with voice , Recognizability builds resistance, and The power of the written word. The modifications were generally perceived to enhance therapeutic experience and effectiveness, albeit participants’ perspectives varied and sometimes contrasted. Conclusions: Findings suggest that refining VRT for persistent voices may involve improving avatar's facial expressions, tailoring therapy to voice experiences, and using recognizable VR environments with gradual exposure and selective visual tools. While controlled studies are needed to establish efficacy, these insights offer practical guidance for VRT refinement and development.

Background: Immersive virtual reality–assisted therapy (VRT) is a relational therapy for distressing voices in psychosis. Like AVATAR therapy (AT), VRT centers on therapist-facilitated dialogues with a digital avatar representing a voice. Unlike AT, VRT uses immersive virtual reality (VR). While participant experiences of AT have been explored, therapist perspectives remain unexamined, and for VRT, neither participant nor therapist experiences have been studied. Understanding these perspectives is essential to inform optimization of therapy, future research, and implementation. Objective: The objective of this qualitative study was to explore both trial participants’ and therapists’ experience of VRT in the Challenge trial. Methods: Semistructured interviews were conducted with 10 trial participants and 8 therapists across the 3 Challenge trial sites. Trial participants were purposively sampled to ensure site representation and variation in voice-hearing duration. Individual interviews were conducted with trial participants, while therapists participated in site-based groups with 2‐3 in each. Interviews were audio-recorded, transcribed, and subjected to reflexive thematic analysis from a critical realist position. Coding and theme development were inductive. People with lived experience were invited to an initial focus group for topic guide development and a later theme validation workshop. Reporting followed the Standards of Reporting Qualitative Research (SRQR). Results: A total of five overarching themes were generated: (1) using technology to meet the voice, (2) a different approach to voice-hearing and treatment, (3) on a tight schedule, (4) a toolbox for transformation, and (5) a price to pay. Trial participants and therapists generally found VRT acceptable, appropriate, and feasible. Highlights included the acknowledging approach to the voice(s), facilitation of engagement with the voice(s), and opportunity to share the otherwise private experience of voice-hearing. Externalizing and embodying the voice(s) in VR-supported avatar role-plays was seen as a key affordance. Positive outcomes included increased trial participant empowerment and self-worth, enabling or improving voice dialogue, new understanding of voice intentions, and changes in voice frequency or content. Challenges included instances of participant anxiety, exhaustion, or suboptimal sense of (voice) presence; adverse voice reactions; technological malfunctions and limitations to avatar design; measurement insensitivity; tensions between assertiveness and compassion; difficulties with reproducing negative voice content; and the demanding nature of the therapy and the nontraditional skills required of therapists. Conclusions: The study provided comprehensive insights into trial participants’ and therapists’ experiences of VRT in the Challenge trial. Findings share several similarities with qualitative research on other relational therapies for distressing voices and highlight VRT’s potential for positive change. Key considerations for future research and implementation include monitoring anxiety and voice reactions, ensuring operational reliability of hardware and software, and addressing the additional effort required by therapists, which may be unsustainable in routine practice. As a demanding intervention, the successful implementation of VRT will require adequate training, supervision, and structural support.

Paranoia is a distressing and prevalent symptom in schizophrenia spectrum disorders. Virtual reality-based cognitive behavioral therapy for paranoia (VR-CBTp) has been proposed to augment behavioral interventions by providing controlled and safe virtual environments in which social situations inducing paranoid anxiety can be manipulated, allowing for new therapeutical possibilities such as gradual exposure and repetition. This assessor-masked, randomized parallel group superiority trial investigated the efficacy of VR-CBTp compared to standard CBTp. Participants were randomized to receive ten sessions of VR-CBTp or CBTp, both on top of treatment as usual. Intention-to-treat analyses included 254 participants (VR-CBTp: n = 126, CBTp: n = 128). Outcomes were assessed at baseline, treatment cessation and follow-up (6 months after treatment cessation). The primary outcome was Ideas of Persecution subscale from the Green Paranoid Thoughts Scale, measured at treatment cessation. There was not a statistically significant between-group difference on the primary outcome at endpoint (effect estimate: 2% in favor of VR-CBTp; 95% confidence interval: −11% to +17%; Cohen’s d = 0.04; P = 0.77, based on exponentiated log-transformed data). No deaths or violent incidents involving law enforcement occurred during the study. In conclusion, VR-CBTp was not superior to CBTp in reducing schizophrenia-spectrum-disorders-related paranoia. ClinicalTrials.gov registration: NCT04902066.

Introduction: The aim of this study was to compare the multidisciplinary vocational intervention, Morpheus, with standard vocational rehabilitation for young adults with incident schizophrenia undergoing the OPUS specialised early intervention programme. The study evaluated whether the type of vocational intervention was related to attachment to the labour market and educational system, outpatient contacts, hospital admissions and psychotropic drug use.Methods: This retrospective cohort study included patients of the OPUS programme in the period from January 1, 2014, to December 31, 2019. Patients at Aarhus University Hospital Psychiatry (Aarhus) were offered the Morpheus intervention, while patients at Aalborg University Hospital (Aalborg) received standard vocational rehabilitation. The study used register and clinical data. The analyses involved logistic and linear regression presented as crude and adjusted models.Results: Of the 404 OPUS patients from Aarhus and 246 OPUS patients from Aalborg, patients participating in the Morpheus intervention (n = 116) were more likely to be employed or enrolled in education 2 and 4 years after diagnosis compared with patients undergoing standard vocational intervention (n = 130). Specifically, the adjusted odds ratio for employment was 1.14 (0.37; 3.45) and 1.51 (0.70; 3.27) at 2 and 4 years, respectively. Morpheus patients were less likely to attend somatic outpatient contacts, which involve consultations or treatment for physical health conditions, as well as psychiatric outpatient contacts. Furthermore, they were less likely to be admitted to somatic departments or to redeem antipsychotic medication. However, Morpheus patients had a higher likelihood of being admitted to psychiatric departments during the periods 0–2 and 2–4 years after diagnosis.Conclusion: Young adults with incident schizophrenia receiving the Morpheus intervention within the OPUS treatment did not show statistically significant increased odds of employment or education enrolment compared to those in standard vocational rehabilitation.

Purpose Work holds significant value in the lives of most individuals, impacting various aspects such as identity, health, and the economy. However, young individuals with schizophrenia often encounter challenges in accessing and maintaining employment. Despite this, knowledge regarding their experiences with labor market is sparse. The study aimed to explore perspectives on labor market affiliation and vocational intervention in relation to quality of life and health among young people with schizophrenia. Methods A qualitative approach was employed, applying individual interviews as data collection method. Twelve patients with first episode of schizophrenia were recruited from two outpatient clinics. Thematic analysis was used, following an inductive process. A user panel was established to ensure quality and relevance of the study. Results Three key themes were identified from the analysis: 1. “Work is simultaneously rewarding and demanding”, highlighting the struggle to balance the benefits of employment with the difficulties of meeting labor market requirements; 2. “Mental health, stigma and work: A complex interplay”, which concerned how work simultaneously contributes to stress and reduces psychiatric symptoms; 3. “Supported employment: Facilitating work-life balance”, concerning how supported employment intervention facilitated a better work-life balance, enhancing overall quality of life, under specific conditions. Conclusion Young individuals with schizophrenia are highly motivated to work, yet encounter significant barriers to labour market participation, related both to their mental health condition and societal stigma. Supported employment programmes emerge as crucial in empowering individuals with schizophrenia to navigate the complexities of the labour market while managing their mental health effectively.

Paranoia is a distressing and prevalent symptom in schizophrenia spectrum disorders (SSD). This assessor-masked, randomized parallel group superiority trial investigated the efficacy of virtual reality-based cognitive behavioral therapy (VR-CBT) compared to standard CBT targeting paranoia. A total of 259 participants with SSD and paranoia were randomized to receive 10 sessions of VR-CBT or standard CBT, excluding five who later withdrew informed consent. Intention-to-treat analyses included 254 participants (VR-CBT: n = 126, standard CBT: n = 128). Outcomes were assessed at baseline, treatment cessation (3 months) and follow-up (9 months). The primary outcome was the Green Paranoid Thought Scale (GPTS) subscale Ideas of Persecution, measured at treatment cessation. Linear mixed-model analyses revealed no statistically significant difference between the groups at endpoint (adjusted mean difference 1.12, 95% CI: -1.75 to 3.99 Cohen’s d=0.10; p=0.44). Both groups demonstrated large with-in group improvements on the primary outcome (VR-CBT: Cohen’s d=0.88; standard CBT: Cohen’s d=0.87). No deaths or violent incidents involving law enforcement occurred during the study. These findings do not support the superiority of VR-CBT over standard CBT; rather, both interventions significantly reduced paranoia and represent promising treatment options for SSD-related paranoia. ClinicalTrials.gov identifier NCT04902066.

Pathogenic variants in the IRF2BPL gene are associated with neurodevelopmental disorders with varying degrees of regression, loss of speech and epilepsy. The phenotype is also known as Neurodevelopmental Disorder with regression, Abnormal Movements, loss of Speech, and Seizures (NEDAMSS). The motor symptoms of this disorder share significant phenotypical characteristics with catatonia, a severe neuropsychiatric psychomotor syndrome. The objective of this article is to expand the knowledge on the presentation of NEDAMSS with a focus on psychiatric symptoms including catatonia. A systematic review of 32 case presentations of NEDAMSS, and a novel case report of a patient with NEDAMSS, exhibiting multiple psychiatric symptoms, including catatonia are presented. Psychiatric symptoms and disorders including affective disorders, psychotic symptoms, catatonia, and developmental disorders are reported in one third of the reviewed cases. Reported effects of pharmacological treatment on motor symptoms of NEDAMSS are very limited. Our case presents improvement in motor symptoms originally attributed to NEDAMSS, after treatment with Lorazepam following diagnosis with catatonia. Patients with NEDAMSS may present with both neurological and psychiatric symptoms. The clinical presentation of NEDAMSS motor symptoms and catatonia have similarities and thus poses significant challenges to the diagnostic process, with risk of incorrect or delayed treatment. The limited experience and the complex phenotype of NEDAMSS complicates pharmacological treatment and encourages caution, especially with the use of antipsychotic drugs in the presence of possible catatonic symptoms.