To Örebro University

INTRODUCTION AND OBJECTIVE: The cholinergic system has broad implications for affective and cognitive processes, which makes it pertinent for the psychopathology and treatment of mental disorders. Questions concerning its role in schizophrenia, a chronic disorder characterized by psychosis, emotional blunting and cognitive deficits, have been made particularly relevant due to the recent Food and Drug Administration (FDA) approval of a muscarinic agonist as an antipsychotic agent. The present paper details the protocol for a scoping review that will map models, evidence and research gaps concerning the role of the cholinergic system in the positive, negative and cognitive domains implicated in the psychopathology of schizophrenia.

METHODS AND ANALYSIS: The scoping review will be conducted according to JBI (formerly the Joanna Briggs institute) methodology, using articles from the following databases: PubMed, Embase, Scopus, Cochrane Central Register of Controlled Trials and PsycInfo. Two independent reviewers will screen the articles using title and abstract, after which full text-analysis will determine inclusion. Only published original peer-reviewed English-language studies from the last 20 years that pertain to the review objective will be included. Clinical studies will be assessed for methodological quality and risk of bias. The results, which the reviewers will extract independently of each other using a data extraction tool, will be presented in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis Protocol Extension for Scoping Reviews (PRISMA-ScR).

DISCUSSION: Clarifying the research gaps in the field can indicate where future pre-clinical and clinical studies and systematic reviews can be worthwhile, and the risk of bias assessment aids in this by stratifying the included clinical trials according to quality. However, the language and publication date restrictions risk excluding relevant studies, which can introduce bias.

INTRODUCTION: Psychiatric disorders are common and significantly impact the quality of life. Inflammatory processes are proposed to contribute to the emergence of psychiatric disorders. In addition to inflammation, disturbances in metabolic pathways have been observed in individuals with different psychiatric disorders. A suggested key player in the interaction between inflammation and metabolism is the Nod-like receptor 3 (NLRP3) inflammasome, and NLRP3 is known to react to a number of specific metabolites. However, little is known about the interplay between these immunometabolites and the NLRP3 inflammasome in mental health disorders.

AIM: To assess the interplay between immunometabolites and inflammasome function in a transdiagnostic cohort of individuals with severe mental disorders.

METHODS: Mass spectrometry-based analysis of selected immunometabolites, previously known to affect inflammasome function, were performed in plasma from low-functioning individuals with severe mental disorders (n = 39) and sex and aged-matched healthy controls (n = 39) using a transdiagnostic approach. Mann Whitney U test was used to test differences in immunometabolites between psychiatric patients and controls. To assess the relationship between inflammasome parameters, disease severity, and the immunometabolites, Spearman's rank-order correlation test was used. Conditional logistic regression was used to control for potential confounding variables. Principal component analysis was performed to explore immunometabolic patterns.

RESULTS: Among the selected immunometabolites (n = 9), serine, glutamine, and lactic acid were significantly higher in the patient group compared to the controls. After adjusting for confounders, the differences remained significant for all three immunometabolites. No significant correlations were found between immunometabolites and disease severity.

CONCLUSION: Previous research on metabolic changes in mental disorders has not been conclusive. This study shows that severely ill patients have common metabolic perturbations. The changes in serine, glutamine, and lactic acid could constitute a direct contribution to the low-grade inflammation observed in severe psychiatric disorders.

In this explorative study, we investigated if an adjunctive treatment with one single dose of the monoclonal antibody rituximab would improve symptoms and function in treatment-resistant patients with schizophrenia spectrum disorder (SSD, n = 9) or obsessive-compulsive disorder (OCD, n = 10), based on the inflammatory hypothesis for mental disorders. Patients were followed for one year. Disability was measured with the Personal and Social Performance score (PSP). At baseline, the mean PANSS score in the SSD group was 99 ± 32 and the mean Y-BOCS score in the OCD group was 27.5 ± 7. Mean PSP scores were 32 ± 10.2 and 42.5 ± 9.9 in the SSD and OCD groups, respectively. Seven had Paediatric Acute-Onset Neuropsychiatric Syndrome (PANS) in retrospect, and 3 SSD patients had schizo-obsessive subtype. 4/8 SSD patients showed a ≥40% reduction in PANSS at endpoint I week 20, however, 7/9 were similarly improved already at week 12. Among the OCD patients, 2/10 showed a ≥35% reduction in Y-BOCS at week 20. Disability was significantly improved only in the SSD group. The percentual decrease of PANSS scores in SSD patients was associated with the increase in immunoglobulin levels week 20 (n = 8: IgG r = 0.85, p = .007; IgA r = 0.79, p = .019; IgM r = 0.73, p = .038). Rituximab was generally well tolerated in these patients. Self-rated improvements since baseline were reported for psychic (p = .021), neurological (p = .059), and autonomic (p < .001) side effects (UKU-SERS-Pat side-effect scale). Anxiety was commonly reported by OCD patients, while an initial increase in psychotic symptoms was seen in a few SSD patients. An RCT is underway to evaluate rituximab in SSD.

Introduction: Immunological mechanisms may contribute to the causation of mental illness. Autoimmunity is most convincingly shown for anti-NMDA-R encephalitis and Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS); disorders that overlap clinically with schizophrenia and OCD. Altered inflammatory cytokine production, glial activation and auto-antibodies have also been associated with schizophrenia and OCD. In these disorders, however, the treatment results with anti-inflammatory or immunomodulating drugs have hitherto been limited and inconsistent. Yet other targets within the immune system may still be effective and new options are warranted for treatment-resistant patients. Rituximab targets B-lymphocytes and is often used in autoimmune disorders such as rheumatoid arthritis, multiple sclerosis and anti-NMDA-R encephalitis.

Objectives: We aimed to investigate whether rituximab is clinically effective, safe and tolerable as add-on therapy in markedly ill, treatment-resistant adult psychiatric patients with schizophrenia or OCD. We also wanted to identify putative mediating mechanisms in treatment responders, such as cytokine changes and functional connectivity (FC).

Methods: In an open pilot study, adults (18-39 years) with treatment-resistant schizophrenia and/or OCD were included. They received an intravenous infusion of rituximab 1000 mg, once at baseline, in addition to their regular psychiatric medication and were followed for 1 year. The main outcome measures were the Positive and Negative Syndrome Scale (PANSS) or Yale-Brown Obsessive Compulsive Scale (Y-BOCS), the Clinical Global Impression-Improvement scale (CGI-I) and the Personal and Social Performance scale (PSP). Treatment response was defined as ≥ 40 % decrease in PANSS or ≥ 35 % decrease in Y-BOCS, and much improved according to CGI-I. Resting-state fMRI was applied at baseline and after 5 months. Plasma cytokines were measured at 0, 3 and 5 months. Cognitive tests and the recently developed PsychoNeuroinflammatory Related Signs and Symptoms Inventory (PNISSI) were used to identify and measure symptoms related to neuro-inflammation and cognitive function.

Results: Nineteen patients were treated with rituximab. 3-5 months after treatment, 6/9 patients with schizophrenia and 1/10 with OCD responded. One schizophrenia patient continues with rituximab every 6 months and has reportedly done well for almost 3 years. No severe side effects were reported apart from recurrent abdominal pain in a schizophrenia patient and one case of post-COVID-19 syndrome. Significant changes of FC were detected in responders only and correlated with PSP changes.

Conclusions: Aberrant B-cell activities may contribute to treatment-resistant schizophrenia and be amenable to treatment with rituximab. However, the results of this pilot study need confirmation in placebo-controlled trials.

Background/Objective: Psychiatric disorders are common and they significantly impact quality of life. It has been proposed that inflammatory processescontribute to the emergence of psychiatric disorders. In addition to inflammation, disturbances in metabolic pathways have been seen in individuals with various psychiatric disorders. At the interface between inflammation and metabolism stands the Nod-like receptor 3 (NLRP3) inflammasome, which is anintracellular protein complex responsible for cleaving members of the interleukin-1(IL-1) to their active forms. The overall aim of this thesis project was tounderstand the interplay between metabolism and inflammation in a transdiagnostic cohort of individuals with severe psychiatric disorders.

Methods: Patients with severe psychiatric disorder (n=39) and age- and sexmatched healthy controls (n=39) were included in the studies. Psychiatric diagnoses, comorbidities, severity, and functioning were measured using a numberof validated assessment scales. Biological parameters, such as circulating immune markers, gene expression, and metabolites were analyzed using electrochemiluminescence immunoassay, qPCR, and UHPLC-MSMS, respectively. 

Results: The results revealed that in individuals with psychiatric disorders, immune cells were primed in regard to the NLRP3 inflammasome, with elevatedinflammasome-related cytokine levels, regardless of diagnosis. In addition, positive metabolic inflammasome regulators, such as lactic acid, serine, and glutamine were significantly higher in the patients; the main metabolic pathwaysthat were affected included arginine and proline metabolism and tryptophan metabolism. A number of these parameters also correlated with the patients’ disease severity. Lastly, the patients as a group displayed transdiagnosticchanges in immune–lipid pathways. In particular, strong associations could beobserved between two triglycerides and one ether phospholipid, with the inflammatory markers osteopontin and IL-1Ra.

Conclusion: Severe psychiatric disorders are associated with changes in the inflammasome system and its corresponding cytokines, as well as with metabolicdysregulation. The data indicate that, while these systems are known to be associated, their interplay seems limited to relatively few inflammatory mediatorsand metabolites in this patient group. Lastly, while large overlaps were seen between different primary diagnoses, unifying, transdiagnostic patterns of inflammatory and metabolic dysregulation were weak; further studies with a largercohort are needed to examine this issue.

Background: Adults with autism spectrum disorder face several barriers to accessing evidence-based care, including difficulties in communicating needs, social anxiety or in traveling to a health care unit. In recent years, several forms of internet-based treatments have shown to be effective for a variety of psychiatric conditions. Internet-based treatment alternatives allow convenient and flexible formats, and therefore have the potential to increase access to health care for individuals with autism spectrum disorder. However, knowledge about how internet-based treatment features may suit the needs of individuals with autism is limited. The aim of this study was to explore the participant experiences of an internet-based intervention for adults with autism spectrum disorder. The primary focus of the investigation was on autism-specific needs in relation to the features unique to the online format.

Methods: In this qualitative study, semi-structured telephone interviews were conducted with 14 participants who had completed a text-based internet-based intervention for adults with autism spectrum disorder. We used an inductive approach and analyzed the data using qualitative content analysis.

Results: Five main categories were identified: (1) implications of the online format, (2) the fixed non-individualized model, (3) therapist interaction, (4) interacting with other participants, and (5) making use of the treatment content. Overall, participants appreciated the availability and that they could work on their treatment independent of time or location. Among those participating in group-based chat-sessions with the other participants, it was considered a generally positive experience. Furthermore, most participants felt safe and relaxed in relation to the therapist and appreciated the text-based format. However, several participants felt that the format and content of the treatment was not sufficiently adapted to their individual life situation.

Conclusion: In conclusion, this internet-based treatment constitutes an accessible and energy-saving treatment alternative for adults with autism. Further, integrating group-based components seems feasible in an otherwise individual internet-based treatment for individuals with autism. However, group-based components do require a clear purpose and rationale. Future studies should develop and evaluate treatment adaptations tailored to individual needs.

Background: Individuals with generalised joint hypermobility (GJH, present in 10–20% of the general population) are at increased risk of being diagnosed with a range of psychiatric and rheumatological conditions. It is unknown whether Paediatric acute-onset neuropsychiatric syndrome (PANS), characterised by childhood onset obsessive-compulsive disorder or restricted eating and typically associated with several comorbid neuropsychiatric symptoms, is associated with GJH. It is also unknown whether extensive psychiatric comorbidity is associated with GJH.

Method: This is a case-control study including 105 participants. We compared three groups: Individuals with PANS, individuals with other mental disorders and healthy controls. Joint mobility was assessed with the Beighton scoring system, psychiatric comorbidity with the M.I.N.I. or MINI-KID interview and symptoms of PANS with the PsychoNeuroInflammatory related Signs and Symptoms Inventory (PNISSI).

Results: Hypermobility was similar across groups, and high rates of psychiatric comorbidity was not associated with higher Beighton scores.

Conclusion: Although GJH is associated with several psychiatric conditions, such as ADHD and anxiety, this does not seem to be the case for PANS according to this preliminary study.

Mental disorders are heterogeneous and psychiatric comorbidities are common. Previous studies have suggested a link between inflammation and mental disorders. This link can manifest as increased levels of proinflammatory mediators in circulation and as signs of neuroinflammation. Furthermore, there is strong evidence that individuals suffering from psychiatric disorders have increased risk of developing metabolic comorbidities. Our group has previously shown that, in a cohort of low-functioning individuals with serious mental disorders, there is increased expression of genes associated with the NLRP3 inflammasome, a known sensor of metabolic perturbations, as well as increased levels of IL-1-family cytokines. In the current study, we set out to explore the interplay between disease-specific changes in lipid metabolism and known markers of inflammation. To this end, we performed mass spectrometry-based lipidomic analysis of plasma samples from low-functioning individuals with serious mental disorders (n = 39) and matched healthy controls (n = 39). By identifying non-spurious immune-lipid associations, we derived a partial correlation network of inflammatory markers and molecular lipids. We identified levels of lipids as being altered between individuals with serious mental disorders and controls, showing associations between lipids and inflammatory mediators, e.g., osteopontin and IL-1 receptor antagonist. These results indicate that, in low-functioning individuals with serious mental disorders, changes in specific lipids associate with immune mediators that are known to affect neuroinflammatory diseases.

The aim of this study was to investigate inflammatory perturbations in 40 patients with severe and complex psychiatric disorders by studying the activity of the NLRP3 inflammasome, with a trans-diagnostic approach. Gene expression of CASP1, NLRP3, PYCARD, IL1B, IL1RN, TNF showed a significant increase in the patient group compared to a matched control group. Plasma levels of IL1Ra, IL-18, TNF, IL-6 and CRP were increased in the patient group. Within the patient group, increased gene expression of inflammatory markers correlated with increased disease severity. The findings support the inflammation hypothesis for markedly ill psychiatric patients across diagnostic groups.

There has been considerable international research on formal coercion in psychiatry in recent decades but less on informal coercion, especially from a staff perspective. This study was based on previous research which identified five forms of coercion in psychiatry: persuasion, interpersonal leverage, inducement, threats and formal coercion. The purpose was to describe the staff's reflections on the forms and the use of informal coercion against patients. We conducted four focus group interviews with psychiatric social workers, psychologists and physicians at four different clinics. The purpose was to create a reflective conversation about informal coercion. The interviews were analysed with qualitative content analysis. In addition to the five previously identified forms of coercion we found three other forms in our material: cheating the patient, an upbringing attitude, and using rules and procedures. Participants also described coercion from other stake-holders such as relatives and other authorities. Other reflections were interpreted as professionalism and coercion, where the participants stressed the importance of staff members' approach to patients, having clear communication with patients, individualized care, and good cooperation with each other and with other stakeholders. According to the participants, informal coercion was often used, but at the same time they were hesitant about using it. The participants had very different views of how patients perceived informal coercion and how interpersonal leverage should be used. They also reported difficulties in dealing with the informal coercion that relatives and other authorities use, as it may threaten the patient's ability to recover. Informal coercion should not only be seen as a legal or clinical issue. The fact that there are important ethical aspects in matters of informal coercion should also be acknowledged.