To Örebro University

Schizophrenia and obsessive-compulsive disorder (OCD) are complex neuropsychiatric disorders with emerging evidence implicating immune and neuroinflammatory mechanisms. This exploratory pilot study investigated aquaporin-4 positive (AQP4+) extracellular vesicles (EVs) in the cerebrospinal fluid (CSF) of 11 treatment-resistant patients with schizophrenia (n = 5) or obsessive-compulsive disorder (OCD, n = 6) receiving an add-on, single-infusion rituximab (1000 mg) treatment, a B-cell depleting therapy. CSF samples were collected pre-treatment and, for a subset, again five months post-treatment. AQP4+ EV levels in CSF were quantified using flow cytometry with antibodies targeting different regions of the AQP4 molecule. We also measured selected cytokines in CSF and plasma and cytokine gene expression in peripheral blood cells. Patients with schizophrenia exhibited higher AQP4+ EV levels compared to those with OCD. In schizophrenia, AQP4+ EVs correlated positively with the inflammatory marker CXCL8/IL-8 but negatively with CSF-TNF-α. Plasma markers CXCL8/IL-8 and TGF-β1 were positively associated with CSF-AQP4+ EVs in schizophrenia. Between 24- and 40-times higher concentrations of CXCL8/IL-8 in CSF than in plasma suggest intrathecal production of this chemokine in both disorders. Post-treatment, AQP4+ EV levels decreased in the patients who improved following rituximab but remained stable in non-responders. These findings suggest that astrocyte-derived extracellular vesicles may play a role in neuroinflammatory processes linked to schizophrenia and possibly also to severe OCD. The observed relationships between AQP4+ EVs and cytokines support the hypothesis that astrocyte-derived EVs could modulate intrathecal immune responses and potentially also interact with peripheral immune mechanisms. Larger studies are warranted to validate these preliminary findings.

Neuroinflammation has been implicated in the pathophysiology of schizophrenia and obsessive-compulsive disorder (OCD) and deviations in brain structure and connectivity are seen in these disorders. Here, we explore the effects of a potent immunomodulatory treatment on neuroimaging. In a pilot study of rituximab treatment in schizophrenia and OCD, a subgroup (n = 13) underwent structural and functional magnetic resonance imaging before and 5 months after treatment, to study longitudinal changes in resting-state functional connectivity (rsFC) and voxel-based morphometry (VBM). A hypothesis-free exploratory whole-brain analysis was performed twice to assess changes in rsFC, using anterior cingulate cortex, anterior insula, posterior insula and nucleus accumbens as seed regions. There were significant interactions (diagnosis x time) in connectivity between right posterior insula and two clusters encompassing basal ganglia and anterior frontal pole, and between left anterior insula and a cluster in basal ganglia, where connectivity decreased in OCD and increased in schizophrenia. The increase of connectivity after rituximab, between left anterior insula and parts of cerebellum and lingual gyrus and between left posterior insula and parts of cerebellum, correlated with improved global psychosocial functioning according to the Personal and Social Performance Scale, especially in schizophrenia. VBM analysis identified two clusters with increased grey matter volumes (GMV) after rituximab, one in right insula overlapping one of the seed regions with significant rsFC changes. This pilot study implies that rituximab may influence both brain structure and connectivity and that GMV changes and rsFC changes are regionally associated.

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.

BACKGROUND: Apathy is one of the most prevalent neurobehavioral manifestations in mild cognitive impairment (MCI) and is included among the behavioral and psychological symptoms of dementia (BPSD). Studies suggest that the presence of apathy could be associated with increased dementia risk. The role of apathy in conversion from MCI to dementia, and whether apathy could be a relevant predictor for dementia progression, are still matters of investigation.

AIM: To study the relationship between apathy and progression to dementia in individuals with MCI.

METHODS: A systematic literature search in Medline, Embase, Cochrane Library, Epistemonikos, PsychINFO, and CINAHL was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The search included longitudinal studies reporting on the association between apathy and dementia.

RESULTS: The main outcome was pooled unadjusted hazard ratios (HR) of apathy in dementia conversion and included 11 studies with 9504 individuals. There was a significant association between apathy and dementia conversion, HR = 1.54; 95% CI, 1.29, 1.84. Subgroup analysis showed a significant association between apathy and progression to AD.

CONCLUSION: Apathy was associated with an increased risk of conversion to AD and all-cause dementia in patients with MCI. The role of apathy as a marker for incident dementia needs to be investigated in large, high-quality studies.

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: The role of inflammation in the aetiology of schizophrenia has gained wide attention and research on the association shows an exponential growth in the last 15 years. Autoimmune diseases and severe infections are risk factors for the later development of schizophrenia, elevated inflammatory markers in childhood or adolescence are associated with a greater risk of schizophrenia in adulthood, individuals with schizophrenia have increased levels of pro-inflammatory cytokines compared to healthy controls, and autoimmune diseases are overrepresented in schizophrenia. However, treatments with anti-inflammatory agents are so far of doubtful clinical relevance. The primary objective of this study is to test whether the monoclonal antibody rituximab, directed against the B-cell antigen CD20 ameliorates psychotic symptoms in adults with schizophrenia or schizoaffective disorder and to examine potential mechanisms. A secondary objective is to examine characteristics of inflammation-associated psychosis and to identify pre-treatment biochemical characteristics of rituximab responders. A third objective is to interview a subset of patients and informants on their experiences of the trial to obtain insights that rating scales may not capture.

METHODS: A proof-of-concept study employing a randomised, parallel-group, double-blind, placebo-controlled design testing the effect of B-cell depletion in patients with psychosis. 120 participants with a diagnosis of schizophrenia spectrum disorders (SSD) (ICD-10 codes F20, F25) will receive either one intravenous infusion of rituximab (1000 mg) or saline. Psychiatric measures and blood samples will be collected at baseline, week 12, and week 24 post-infusion. Brief assessments will also be made in weeks 2 and 7. Neuroimaging and lumbar puncture, both optional, will be performed at baseline and endpoints. Approximately 40 of the patients and their informants will be interviewed for qualitative analyses on the perceived changes in well-being and emotional qualities, in addition to their views on the research.

DISCUSSION: This is the first RCT investigating add-on treatment with rituximab in unselected SSD patients. If the treatment is helpful, it may transform the treatment of patients with psychotic disorders. It may also heighten the awareness of immune-psychiatric disorders and reduce stigma.

TRIAL REGISTRATION: NCT05622201, EudraCT-nr 2022-000220-37 version 2.1. registered 14th of October 2022.