Background Mental disorders are highly prevalent, and they significantly impact individuals and society. Patients experiencing long-term, severe mental disorders with functional impairment and reduced quality of life often have a history of adolescent onset anxiety and depressive disorders. Despite the long-term costs to both patients and society, studies examining treatment effects over time and across diagnoses are scarce. Objective The Norwegian Adult Mental Health Registry (NAMHR) aims to systematically reuse health data to monitor and improve treatment outcomes, patient safety, health service quality, and research. The registry addresses the need for comprehensive data on the effects and utility of mental health services, interventions, and therapy variants in specialized mental health care. Methods The NAMHR is a nationwide naturalistic registry, including all Norwegian adults eligible for treatment in specialized mental health care services who have not opted out. Patients are automatically enrolled when treated in these services. The population includes patients treated in public specialized services and those treated in private services having a contract with public health services. The registry is based on secondary data from the Norwegian Patient Registry (NPR), patient-reported outcome measures (PROMs), patient-reported experience measures (PREMs), the Norwegian Registry for Primary Health Care (KPR), and several other sources, including electronic health records (EHRs). Data linkage uses unique national identity numbers, ensuring high-quality data. The registry collects information on diagnoses, treatments, medication, and patient-reported outcomes, providing a holistic approach to mental health care. Statistical analyses will be defined in each project. Results As of December 2025, the NAMHR is approved and is being constructed. The registry anticipates enrolling up to 170,000 participants, with a new incidence rate of around 10,000 patients per year. Key predictors and outcomes include PROMs and PREMs, and automatically reported measures involving a wide range of data, including EHR data from inpatient and outpatient treatments, data from primary health care, data on job and education status, and data on cause of death. Enrollment is planned to start in 2026, initially by adding journal data and patient-reported data. Other sources will be included. The NAMHR has no planned end date. Results will be made available for internal quality improvement purposes, and data for research are expected to be available around mid-2026 for approved projects. Conclusions The NAMHR will promote quality improvement initiatives and research, including registry-based randomized clinical trials. It will also be possible to link the NAMHR to a similar registry for children and adolescents, making it possible to follow patients from birth to death and supporting the monitoring of diagnostic drift. The NAMHR will inform health policy decisions at local, regional, national, and international levels, contributing to the evaluation and development of clinical guidelines and enhancing personalized treatment approaches. Trial Registration ClinicalTrials.gov NCT06115200; https://clinicaltrials.gov/study/NCT06115200 International Registered Report Identifier (IRRID) PRR1-10.2196/82696

OBJECTIVE:Antipsychotic drugs are to varying degrees associated with hematological side-effects and peripheral metabolic and immunological changes. Here, we aimed to characterize the initial transcriptional changes in peripheral leukocytes from individuals with schizophrenia spectrum disorder (SSD) after starting antipsychotic treatment with amisulpride, aripiprazole, or olanzapine. METHODS:We analyzed RNA sequencing data obtained from peripheral whole blood samples from 100 individuals with SSD (41 antipsychotic-naïve [AP-naïve], 10 AP-free, and 49 AP-switching at inclusion) collected at baseline and after 1 and 3 weeks of antipsychotic drug use. Data from 36 healthy controls (HC) collected at baseline and after 3 weeks without any intervention were included. We analyzed age- and sex-adjusted differentially expressed genes between SSD and HC before and after treatment and stratified by previous antipsychotic use. A linear mixed model was applied to study longitudinal gene expression changes associated with the antipsychotic drug that was used. RESULTS:After 3 weeks of antipsychotic use, the AP-switching group had the most significant transcriptional changes, characterized by increased expression of genes typically transcribed by immature erythroid cells and immature neutrophil cells. This gene profile showed no correlation with symptoms score. Interestingly, the immature neutrophil-associated gene signature was more pronounced in participants receiving olanzapine, and partly also amisulpride, but not aripiprazole. In contrast, only minor transcriptional changes were observed in the AP-naïve participants. CONCLUSIONS:These findings suggest that prior antipsychotic exposure may have a priming effect on leukocyte gene expression, which results in a transcriptional response indicative of stress erythropoiesis and neutropoiesis when switching to a new antipsychotic drug. This response appears to be independent of psychosis symptom severity.

Background Schizophrenia is associated with inflammation. Antipsychotic drugs have anti-inflammatory properties but few antipsychotics have been compared head-to head. The aim of this study was to evaluate the immunomodulatory effects of three pharmacologically different atypical antipsychotics, amisulpiride, aripiprazole and olanzapine, in patients with schizophrenia-spectrum disorders. Methods The study reports a predefined secondary outcome of the BeSt InTro-study, a double blind randomized head-to-head trial comparing amisulpride, aripiprazole and olanzapine. Patients with a schizophrenia-spectrum disorder (N=144) were randomized to the different treatment arms, and serum levels of nine cytokines (interleukin [IL]-1β, IL-2, IL-4, IL-6, IL-10, IL-12p70, IL-17A, interferon [IFN]-γ, and tumor necrosis factor [TNF]-α) were assessed at baseline and weeks 1, 3, 6, 12, 26, 39 and 52. A combined pro-inflammatory variable was constructed from IL1-β and TNF-α. The primary analyses were done in per protocol (PP) data in the drug-naïve sample (n = 56). Changes in cytokine levels between baseline and the end of the study were analyzed in a mixed effects model with amisulpride as the reference drug. Results Treatment with amisulpride was associated with a reduction in pro-inflammatory IL-1β levels over 12 months, this change was statistically different compared to the change in aripiprazole and olanzapine. A significant difference between the influence of amisulpride compared to aripiprazole on the anti-inflammatory cytokine IL-10 was detected. Aripiprazole reduced IL-12p70 more than amisulpride. The combined pro-inflammatory variable decreased from baseline to week 52 with a magnitude of 0.52 standard deviation (SD) after treatment with amisulpride.. Conclusion Patients treated with amisulpride showed greater anti-inflammatory changes in cytokine serum levels than those treated with aripiprazole or olanzapine. Funding The Research Council of Norway, the Western Norway Regional Health Trust, and Klinbeforsk supported the study.

BACKGROUND:Schizophrenia patho-etiology may involve endothelial inflammation and blood-brain barrier (BBB) dysregulation with cellular adhesion molecules (CAMs) as important mediators. CAMs are essential for cellular integrity but can show increased levels in inflammation. Cognitive dysfunction precedes and exists independently of psychotic symptoms in schizophrenia patients. CAMs could impact cognition through influence on BBB integrity. To gain insights into disease mechanisms and potential therapeutic targets, we explored the relationship between CAMs protein levels and neurocognitive tests in schizophrenia-spectrum disorders in the BeSt InTro study. METHODS:Seventy-one in- and out-patients underwent CAMs measurements and neuropsychological testing on a minimum of one time point: baseline, 6, 26, or 52 weeks. Cognitive domains included working memory, processing speed, verbal abilities, executive functions, and overall cognition. CAMs analyzed were neural CAMs: junctional adhesion molecule (JAM-A) and neural cadherin (N-CAD); vascular CAMs: intercellular adhesion molecule (ICAM)-1, vascular adhesion molecule (VCAM)-1, mucosal addressin cell adhesion molecule (MADCAM), and platelet (P)-selectin from fasting blood samples. Linear mixed effects models, adjusted for age, sex, body mass index, smoking, education, and drug naivety, estimated CAMs effect on cognitive outcome measures. RESULTS:N-CAD levels correlated positively with overall cognition (p = 0.002), working memory (p = 0.034), and executive functions (p = 0.0011). ICAM-1 levels correlated positively with overall cognition (p = 0.037). Conversely, JAM-A levels correlated negatively with executive functions (p = 0.021). CONCLUSION:Associations between CAMs (N-CAD, ICAM-1, JAM-A) and neurocognitive tests suggest CAMs may impact cognition in schizophrenia. Contrary to our hypothesis, most associations between CAMs levels and cognitive tests were positive. Future research on mechanisms is mandatory.

BACKGROUND:Impaired clinical insight is common in schizophrenia spectrum disorders (SSDs) and predicts poor treatment adherence and outcomes. It is linked to disorganised, positive, negative, and hostility symptoms. However, few studies repeatedly assess insight after antipsychotic initiation while comparing pharmacologically distinct agents. This study examined how symptom levels and changes predict the development and endpoint of clinical insight over 6 weeks, contrasting the partial dopamine agonist aripiprazole (PDA) with two dopamine antagonists (DAs). METHODS:Data from 144 SSD patients in the Bergen-Stavanger-Innsbruck-Trondheim (BeSt InTro) trial, a pragmatic, semi-randomised study of amisulpride, aripiprazole, and olanzapine, were analysed using latent growth curve models. Insight was measured by PANSS Item G12; symptom factors (positive, negative, hostility, cognitive/disorganised) were derived from PANSS. RESULTS:Lower baseline symptoms and greater improvement between weeks 3 and 6 predicted better insight at 6 weeks across all factors. For positive symptoms, improvement between weeks 1 and 3 (b = 0.57, p = 0.009) also predicted better insight. Patients on aripiprazole showed less improvement in insight, though some findings lost significance after correction. CONCLUSION:Symptom reduction is associated with improved insight, with early changes in positive symptoms exerting the fastest effect. Despite symptom improvement, aripiprazole PDA treatment was linked to less insight gain than DA treatment. These preliminary findings warrant further study.

Research on sustainment of implemented evidence-based practices (EBPs) for people with psychosis has been limited in mental health services. This prospective cohort study extended a cluster-randomized trial (trial registration number NCT03271242) of implementation of four EBPs in Norwegian mental health services. In the trial 39 clinical units were randomized to receive implementation support for one of two chosen EBPs. This study aimed to measure sustainment for two biological EBPs (physical health care, antipsychotic medication management) and two psychosocial EBPs (family psychoeducation, illness management and recovery), and to explore factors influencing sustainment. Fidelity to the EBP with implementation support was measured after 18 months of implementation support and at 36 months (18 months post-implementation), additionally key informants reported factors influencing sustainment. Among 27 sites with high or moderate fidelity at 18 months, 20 (74%) sustained the practice at the same or higher level at 36 months; 10 of 13 sites, most with psychosocial EBPs, sustained high fidelity, and 10 of 14 sites, most with biological EBPs, sustained moderate fidelity. Sustaining sites demonstrated significantly greater efforts to continue the EBP, while non-sustaining sites encountered greater barriers including leadership change or key clinician turnover. With efforts to continue the EBP, most sites sustained the practice with high fidelity for psychosocial EBPs and moderate fidelity for biological practices. A clinical director or champion determined to continue the practice together with a trained clinical staff were the two main ingredients for sustainment.

Background There are substantial sex differences in schizophrenia. However, research addressing sex differences regarding the antipsychotic effect on the immune system is lacking. The aim of our study was to compare changes in cytokine levels in men and women with schizophrenia spectrum disorder over 12 months of treatment with antipsychotics. Methods This study reports pre-planned secondary outcomes from the BeSt InTro Study – a pragmatic, semi-randomised, rater-blinded comparison of amisulpride, aripiprazole, and olanzapine. The groups were analysed collectively. Of the 144 enrolled patients with schizophrenia spectrum disorders and ongoing psychosis, 56 were antipsychotic-naïve at baseline (20 women and 36 men) and were included in this study. Blood samples from these 56 patients were drawn at baseline, prior to treatment with antipsychotics, and 1, 3, 6, 12, 26, 39, and 52 weeks after initiation of antipsychotic medication. Duration of treatment was 52 weeks. Serum cytokine levels were assessed with a multiplex immunoassay. Changes in the levels of IL-4, IL-6, TNF-α, IL-1β, IL-2, IL-10, IL-12p70, IL-17A, IFN-γ and CRP from baseline to the different follow-up times were analysed using linear mixed effects models separately for men and women, and then compared. Outcomes Cytokine levels were mainly stable in men during the study period. In women, IL-4 levels were lower at baseline compared with men (p=0.048) and showed a consistent and significant increase at weeks 6 (p=0.006), 26 (p<0.001), 39 (p=0.002), and 52 (p=0.001). TNF-α increased in women at weeks 26 (p=0.008) and 39 (p=0.012). IL-6 had a transient increase in women at weeks 12 (p=0.003) and 26 (p=0.007). There were significant sex differences in progression of cytokine levels at weeks 3 (IL-6: p=0.046), 6 (IL-4: p=0.022, IL-6: p=0.015), 12 (IL-6: p=0.01), 26 (IL-4: p<0.001, IL-6: p=0.015, TNF-α: p=0.026), 39 (IL-4: p=0.003, TNF-α: p=0.023) and 52 (IL-4: p<0.001, TNF-α: p=0.009). CRP levels did not differ between sexes at baseline or during the study period and did not change significantly during treatment with antipsychotics in either sex. Interpretation We found significant sex differences in serum cytokine changes in drug-naïve patients with schizophrenia during treatment with antipsychotics. Cytokine levels were mainly altered in women, with increased IL-4, IL-6, and TNF-α levels. Cytokine changes may dramatically affect mental as well as somatic health. Our findings add to already established sex differences in schizophrenia pathophysiology and might have a potential role for future treatment guidelines. Funding The Research Council of Norway, the Western Norway Regional Health trust, and the participating hospitals and universities provided funding for this study.

Childhood maltreatment and trauma (CMT) increase the risk for schizophrenia spectrum disorders (SSDs) and the severity of psychosis symptoms. Few studies have considered the possible influence of parental mental health on the relationship between CMT and symptoms of psychosis. Possibly, parental mental health problems (MHP) confound this relationship by increasing both the genetic vulnerability for psychosis and the potential for sub-optimal childhood environments. The aim was to examine the potential influence of parental MHP on the relationship between CMT and symptoms of psychosis. We hypothesized a positive and dose-dependent association between overall CMT and symptoms of psychosis not moderated by parental MHP. Patients with SSDs (N = 133) from the Bergen-Stavanger-Innsbruck-Trondheim (BeStInTro) study were included and assessed for CMT by the Childhood Trauma Questionnaire - Short Form, psychosis symptoms by The Positive and Negative Syndrome Scale and parental mental health by means of focused patient interviews. Regression analyses showed a dose-response relationship between CMT and overall psychosis symptom severity and negative symptom severity, further supported by t-tests showing that SSD patients with CMT showed more psychosis symptoms compared to SSD patients with no CMT. Multiple regression analysis with interaction term showed that the association between CMT and psychosis symptom severity was independent, and not moderated, by parental MHP. A dose-dependent relationship between CMT and psychosis symptoms emerged, not moderated by parental MHP, suggesting that CMT has an independent and true effect on psychosis symptoms.

Implementation of evidence-based practices (EBPs), measured as fidelity to the EBP model, is generally expected to yield significant positive clinical outcomes. However, this association has only partially been established for EBPs used in psychosis treatment. From a cluster-randomized controlled trial (CRCT), we previously reported on the effects of implementation support for four EBPs for psychosis, using fidelity as the measure of implementation success. The current secondary, exploratory study used data from the non-blinded CRCT parent study to investigate the associations between patient- and clinician-reported outcomes and fidelity for these four EBPs. Clinical outcomes were measured in a cohort of 325 patients over three six-month periods. Primary outcomes were BASIS-24 (patient-reported) and HoNOS (clinician-reported). Secondary outcomes were selected subscales of these two measures. The EBPs were Physical Health Care, Antipsychotic Medication Management, Family Psychoeducation, and Illness Management and Recovery. In the CRCT, each of 39 clinical units across six health trusts selected two EBPs for implementation. Units were randomized to the intervention group (implementation support) for one EBP and the control group (written manual) for the other. Fidelity of the four EBPs was measured at baseline and every six months for 18 months. We analyzed the associations between outcomes and fidelity using linear mixed models. BASIS-24 and HoNOS showed improvements for the total sample at 6 and 12 months, and two patient-reported subscales, Symptoms and Relationships, showed improvement at 6 months within two different EBP subsamples. However, no positive associations were found between secondary outcomes and EBP fidelity. Despite some improvements in primary and secondary outcomes over the first 6 to 12 months, we found no positive associations between outcomes and fidelity. Sample size, attrition, trial design, variance in variables, measurement properties, and low exposure, as well as interaction between such factors, might have contributed to our failure to find positive associations between outcomes and fidelity. Future studies of the association between outcomes and fidelity should involve large samples, use outcome and exposure measures closely related to the EBPs, and track cohorts from the beginning of treatment. ClinicalTrials NCT03271242, retrospectively registered 31 August 2017.

Treatment with antipsychotics (APs) for schizophrenia spectrum disorders (SSDs) is generally effective, however, a significant proportion does not respond favorably. Childhood trauma (CT) subtypes (physical, sexual, and emotional abuse, physical and emotional neglect) could influence treatment effectiveness; however, research is scarce. Heterogeneity in AP response could be explained by differentiating by CT subtype. The present study was based on the Bergen-Stavanger-Trondheim-Innsbruck (BeSt InTro) study. CTQ-SF assessed CT subtypes in SSDs (n = 98). CT subtypes were examined in relation to psychosis symptoms measured by PANSS during one year of treatment with APs, by means of linear mixed effects (LME) models. Results were significant for CT subtypes, where increased levels of sexual abuse and physical neglect were associated with increased mean levels of psychosis symptoms throughout the course of treatment from baseline to 52 weeks. AP effectiveness may thus be influenced by CT subtype in SSDs. The results support clinical guidelines recommending a focus on assessment and treatment of trauma in SSDs.

Kjelby, Eirik PhD; Gjestad, Rolf PhD; Fathian, Farivar PhD; Sinkeviciute, Igne PhD; Alisauskiene, Renata MD; Anda, Liss-Gøril PhD; Løberg, Else-Marie PhD; Reitan, Solveig Klæbo PhD; Joa, Inge PhD; Larsen, Tor Ketil PhD; Rettenbacher, Maria PhD; Berle, Jan Øystein PhD; Fasmer, Ole Bernt PhD; Kroken, Rune Andreas PhD; Johnsen, Erik PhD Author Information

IntroductionIt is known from the literature that men are slower to seek help and staying engaged in mental health care compared to women. Seeing that in psychosis, men more often than women have insidious onsets but also a more malign illness course, it is important to find ways to improve timely help-seeking. The aim of this study was to explore barriers and facilitators for help-seeking in young male persons struggling with early signs of psychosis.MethodsQualitative interviews with nine young men who suffer from a first episode of psychosis or psychosis risk symptoms.ResultsMale stereotypical ideals, significant others, and knowledge of symptoms and where to get help as well characteristics of symptom trajectories appeared to be important determinants of help-seeking behavior.DiscussionInterviews indicated that help-seeking in the participants was delayed first, because of reluctancy to disclose distress and second, because significant others were unable to accurately recognize symptoms. Information, awareness, and easy access to care remain important in early detection and intervention in psychosis and psychosis risk. However, more emphasis should be placed on de-stigmatizing mental health problems in men and aiming information specifically at them.

Suicide is a common cause of death in all phases of schizophrenia spectrum disorder, particularly in the youngest patients. Clinical measures have demonstrated limited value in suicide prediction, spurring the search for potential biomarkers. The causes of suicidal behaviour are complex, but the immune system seems to be involved as it reflects or even causes mental suffering. We aimed to identify cytokines with associations to suicidality in a sample of patients with symptoms of active psychosis. Patients with schizophrenia spectrum disorder (N = 144) participating in a semi-randomized antipsychotic drug trial (the BeSt InTro study) were assessed with the Positive and Negative Syndrome Scale (PANSS) and the Calgary Depression Scale for Schizophrenia (CDSS) at eight visits across 12 months. The Clinical Global Impression for Severity of Suicidality scale (CGI-SS) was used for assessing suicidality. Serum concentrations of tumour necrosis factor (TNF)-alpha, interferon (IFN)-gamma, interleukin (IL)-1beta, IL-2, IL-4, IL-6, and IL-10 were measured using immunoassays. A logistic regression model was used to investigate the association between cytokine levels and suicidality. To enhance clinical significance, the CGI-SS scores were dichotomized into two groups before analyses: low (=1) and high (≥2) risk for suicidality. Both uni- and multi-variate analyses revealed an inverse correlation between IL-2 and IL-10 serum levels and suicidality, where lower cytokine concentrations of IL-2 and IL-10 were associated with higher suicidality scores. The results were consistent when adjusted for depression and substance use. These results indicate that inflammatory processes are linked to the risk of suicidality in patients with schizophrenia spectrum disorders.

AIM:The aim of this paper is to present 25 years of clinical experience with family psychoeducation (FPE) work at Stavanger University Hospital in Norway, highlighting the lessons learned in overcoming implementation barriers in publicly funded specialized mental health care. METHODS:This retrospective analysis reviews the integration and sustainability of FPE work within the hospital's standard treatment protocols for psychosis, tracing its origins from the Early Treatment and Intervention in Psychosis (TIPS) study (1997-2000) to its current application. The paper examines key strategies for successful implementation, including staff training and resource allocation, as emphasized by international research. RESULTS:Stavanger University Hospital has successfully implemented and maintained both multi- and single-family FPE approaches over the past 25 years. Initially part of the TIPS study, FPE has been integrated into routine clinical practice for treating psychosis and has recently been extended to families of patients with other severe mental disorders. The sustained success at Stavanger University Hospital is attributed to consistent staff training and the prioritization of sufficient resource allocation. DISCUSSION:The successful and sustainable integration of FPE at Stavanger University Hospital is relatively unique. International guidelines recommend FPE for psychosis, but its implementation remains inconsistent globally, despite over 50 years of supporting evidence. The hospital's experience underscores the critical role of continuous training and dedicated resources in embedding FPE into regular clinical practice. These findings suggest that addressing these areas can significantly enhance the uptake of FPE in other clinical settings. CONCLUSION:The 25-year experience at Stavanger University Hospital demonstrates that with appropriate training and resources, FPE can be successfully integrated and sustained within standard mental health care practices. This case study provides valuable insights for other institutions aiming to implement FPE and improve treatment outcomes for patients with severe mental disorders.

Background: Despite the large amount of leadership and implementation theories and recommendations, healthcare services continue to struggle with efficiently incorporating new knowledge. The questioning of conventional leadership approaches in healthcare organizations prompted us to investigate how frontline leaders comprehend their own implementation intentions and actions, and how these intentions and actions may impact the implementation of clinical guidelines in mental healthcare in Norway. Methods: Employing a theory-driven qualitative design, we conducted nine semi-structured interviews with frontline leaders who had recently led implementation of clinical guidelines for the treatment of psychosis in mental health. We employed Systematic Text Condensation, informed by Normalization Process Theory, to structure and analyze the data and used fidelity scales to measure the degree of implementation and distinguish between leaders' levels of success in implementation. Results: Frontline leaders in units that achieved high success in implementation described their intentions and actions differently, from those with less success. The former group's actions aligned more closely with the constructs of the Normalization Process Theory compared to the latter group when describing their actions. Frontline leaders leading units with a high degree of implementation success describe relation-orientation, trust, and providing adaptive space for staff members to take initiative. In contrast, those leading units with less implementation success describe more control and guidance of co-operators and place more emphasize on information and knowledge. Conclusion: Differences in how frontline leaders describe their actions and intentions to achieve clinical guideline implementation suggest that the leadership approach of these frontline leaders is an important factor to consider when planning and conducting implementation. To better understand the implementation process, it is important to pay attention to how frontline leaders customize their leadership approaches to the dynamics of complex organizations, and how they interact with their team and superiors. Plain Language Summary: Despite the large amount of available implementation theories and recommendations, healthcare services continue to struggle with efficiently incorporating new and better practice. The clinicians' closest leader, the Frontline leader, is considered to be in a unique position to manage and enable implementation in the complex healthcare system. The current study's aim was to improve our understanding of what these leaders do, and how they operate, to enable the implementation of clinical guidelines. We interviewed nine mental health service leaders in Norway with experience of leading implementation of clinical guideline during the last 3 years. We found a variety of leaders' intentions and actions regarding their involvement in the process and how they relate to their staff and superiors. Frontline leaders that lead units with high degree of implementation success described actions according to all four constructs of the Normalization Process Theory (Coherence, Cognitive participation, Collective action and Reflexive monitoring), while frontline leaders with less implementation success had more fragmented descriptions. Successful leaders appear to be more relation-oriented compared to those in less successful units. This suggests that leaders should focus on inter-personal dynamics, in addition to more concrete implementation interventions, to succeed. We recommend to take the leadership actions and intentions identified in this study into consideration when planning and evaluating implementation projects and leadership programs, as well as when recruiting frontline leaders.