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Thunberg, P., Reingardt, M., Rode, J. & Msghina, M. (2024). Categorical and dimensional aspects of stimulant medication effects in adult patients with ADHD and healthy controls. Frontiers in Pharmacology, 15, Article ID 1412178.
Open this publication in new window or tab >>Categorical and dimensional aspects of stimulant medication effects in adult patients with ADHD and healthy controls
2024 (English)In: Frontiers in Pharmacology, E-ISSN 1663-9812, Vol. 15, article id 1412178Article in journal (Refereed) Published
Abstract [en]

Psychiatric disorders are categorized on the basis of presence and absence of diagnostic criteria using classification systems such as the international classification of diseases (ICD) and the diagnostic and statistical manual for mental disorders (DSM). The research domain criteria (RDoC) initiative provides an alternative dimensional framework for conceptualizing mental disorders. In the present paper, we studied neural and behavioral effects of central stimulant (CS) medication in adults with attention deficit hyperactivity disorder (ADHD) and healthy controls using categorical and dimensional stratifications. AX-Continuous Performance Task (AX-CPT) was utilized for the later purpose, and participants were classified as "reactive" or "proactive" based on their baseline proactive behavioral index (PBI). Out of the 65 individuals who participated (33 healthy controls and 32 patients with ADHD), 53 were included in the final analysis that consisted of 31 healthy controls and 22 ADHD patients. For the dimensional stratification, a median split of PBI scores divided participants into "reactive" and "proactive" groups irrespective of whether they had ADHD or not. Participants performed AX-CPT in conjunction with functional magnetic resonance imaging (fMRI) before and after CS medication. We found no significant within or between group CS effect when participants were categorically assigned as healthy controls and ADHD patients. For the dimensional stratification, however, CS selectively increased activation in frontoparietal cognitive areas and induced a shift towards proactive control mode in the reactive group, without significantly affecting the proactive group. In conclusion, the neural and behavioral effects of CS were more clear-cut when participants were stratified into dimensional groups rather than diagnostic categories.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2024
Keywords
cognitive control, central stimulants, ADHD, AX-CPT, proactive behavioral index
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:oru:diva-115210 (URN)10.3389/fphar.2024.1412178 (DOI)001274860000001 ()39050752 (PubMedID)2-s2.0-85199411820 (Scopus ID)
Funder
Nyckelfonden, OLL 935421Region Örebro County, OLL 973230
Available from: 2024-08-03 Created: 2024-08-03 Last updated: 2024-08-15Bibliographically approved
Greenfield, M. S., Wang, Y., Hamilton, J. P., Thunberg, P. & Msghina, M. (2024). Emotional dysregulation and stimulant medication in adult ADHD. Journal of Psychiatry & Neuroscience, 49(4), E242-E251
Open this publication in new window or tab >>Emotional dysregulation and stimulant medication in adult ADHD
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2024 (English)In: Journal of Psychiatry & Neuroscience, ISSN 1180-4882, E-ISSN 1488-2434, Vol. 49, no 4, p. E242-E251Article in journal (Refereed) Published
Abstract [en]

Background: Emotional dysregulation affects up to two-thirds of adult patients with attention-deficit/hyperactivity disorder (ADHD) and is increasingly seen as a core ADHD symptom that is clinically associated with greater functional impairment and psychiatric comorbidity. We sought to investigate emotional dysregulation in ADHD and explored its neural underpinnings.

Methods: We studied emotion induction and regulation in a clinical cohort of adult patients with ADHD before and after a stimulant challenge. We compared patients with age- and gender-matched healthy controls using behavioural, structural, and functional measures. We hypothesized that patients would demonstrate aberrant emotion processing compared with healthy controls, and sought to find whether this could be normalized by stimulant medication.

Results: Behaviourally, the ADHD group showed reduced emotion induction and regulation capacity. Brain imaging revealed abberant activation and deactivation patterns during emotion regulation, lower grey-matter volume in limbic and paralimbic areas, and greater grey-matter volume in visual and cerebellar areas, compared with healthy controls. The behavioural and functional deficits seen in emotion induction and regulation in the ADHD group were not normalized by stimulant medication.

Conclusion: Patients with ADHD may have impaired emotion induction and emotion regulation capacity, but these deficits are not reversed by stimulant medication. These results have important clinical implications when assessing which aspects of emotional dysregulation are relevant for patients and if and how traditional ADHD pharmacotherapy affects emotion induction and emotion regulation.

Place, publisher, year, edition, pages
Ovid, 2024
National Category
Neurology Psychiatry
Identifiers
urn:nbn:se:oru:diva-115503 (URN)10.1503/jpn.240009 (DOI)001288854600001 ()39122408 (PubMedID)2-s2.0-85201064035 (Scopus ID)
Funder
Nyckelfonden, OLL - 787911, 93542Region Örebro County
Available from: 2024-08-21 Created: 2024-08-21 Last updated: 2024-08-21Bibliographically approved
Thunberg, P., Fresnais, D., Hamilton, P., Bejerot, S. & Humble, M. B. (2024). Immunomodulatory treatment may change functional and structural brain imaging in severe mental disorders. Brain, Behavior, and Immunity - Health, 41, Article ID 100864.
Open this publication in new window or tab >>Immunomodulatory treatment may change functional and structural brain imaging in severe mental disorders
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2024 (English)In: Brain, Behavior, and Immunity - Health, E-ISSN 2666-3546, Vol. 41, article id 100864Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Elsevier, 2024
Keywords
Functional magnetic resonance imaging, Immunopsychiatry, Neuroinflammation, Obsessive-compulsive disorder, Resting state functional connectivity, Rituximab, Schizophrenia, Voxel-based morphometry
National Category
Psychiatry
Identifiers
urn:nbn:se:oru:diva-116449 (URN)10.1016/j.bbih.2024.100864 (DOI)001319797800001 ()39350952 (PubMedID)2-s2.0-85204368404 (Scopus ID)
Funder
Nyckelfonden, OLL-878311Nyckelfonden, OLL-779081Torsten Söderbergs stiftelse, M84/19The Swedish Brain Foundation, FO2019-0094
Available from: 2024-10-02 Created: 2024-10-02 Last updated: 2024-10-02Bibliographically approved
Lidén, M., Spahr, A., Hjelmgren, O., Bendazzoli, S., Sundh, J., Sköld, M., . . . Thunberg, P. (2024). Machine learning slice-wise whole-lung CT emphysema score correlates with airway obstruction. European Radiology, 34(1), 39-49
Open this publication in new window or tab >>Machine learning slice-wise whole-lung CT emphysema score correlates with airway obstruction
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2024 (English)In: European Radiology, ISSN 0938-7994, E-ISSN 1432-1084, Vol. 34, no 1, p. 39-49Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES: Quantitative CT imaging is an important emphysema biomarker, especially in smoking cohorts, but does not always correlate to radiologists' visual CT assessments. The objectives were to develop and validate a neural network-based slice-wise whole-lung emphysema score (SWES) for chest CT, to validate SWES on unseen CT data, and to compare SWES with a conventional quantitative CT method.

MATERIALS AND METHODS: Separate cohorts were used for algorithm development and validation. For validation, thin-slice CT stacks from 474 participants in the prospective cross-sectional Swedish CArdioPulmonary bioImage Study (SCAPIS) were included, 395 randomly selected and 79 from an emphysema cohort. Spirometry (FEV1/FVC) and radiologists' visual emphysema scores (sum-visual) obtained at inclusion in SCAPIS were used as reference tests. SWES was compared with a commercially available quantitative emphysema scoring method (LAV950) using Pearson's correlation coefficients and receiver operating characteristics (ROC) analysis.

RESULTS: SWES correlated more strongly with the visual scores than LAV950 (r = 0.78 vs. r = 0.41, p < 0.001). The area under the ROC curve for the prediction of airway obstruction was larger for SWES than for LAV950 (0.76 vs. 0.61, p = 0.007). SWES correlated more strongly with FEV1/FVC than either LAV950 or sum-visual in the full cohort (r =  - 0.69 vs. r =  - 0.49/r =  - 0.64, p < 0.001/p = 0.007), in the emphysema cohort (r =  - 0.77 vs. r =  - 0.69/r =  - 0.65, p = 0.03/p = 0.002), and in the random sample (r =  - 0.39 vs. r =  - 0.26/r =  - 0.25, p = 0.001/p = 0.007).

CONCLUSION: The slice-wise whole-lung emphysema score (SWES) correlates better than LAV950 with radiologists' visual emphysema scores and correlates better with airway obstruction than do LAV950 and radiologists' visual scores.

CLINICAL RELEVANCE STATEMENT: The slice-wise whole-lung emphysema score provides quantitative emphysema information for CT imaging that avoids the disadvantages of threshold-based scores and is correlated more strongly with reference tests than LAV950 and reader visual scores.

KEY POINTS: • A slice-wise whole-lung emphysema score (SWES) was developed to quantify emphysema in chest CT images. • SWES identified visual emphysema and spirometric airflow limitation significantly better than threshold-based score (LAV950). • SWES improved emphysema quantification in CT images, which is especially useful in large-scale research.

Place, publisher, year, edition, pages
Springer, 2024
Keywords
Deep learning, Lung, Pulmonary disease, chronic obstructive, Pulmonary emphysema, Tomography, X-ray computed
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:oru:diva-107501 (URN)10.1007/s00330-023-09985-3 (DOI)001188090600001 ()37552259 (PubMedID)2-s2.0-85167352439 (Scopus ID)
Funder
Örebro UniversityNyckelfonden, OLL-881491Region Örebro County, OLL-959996Swedish Heart Lung FoundationKnut and Alice Wallenberg FoundationSwedish Research CouncilVinnovaUniversity of GothenburgRegion Västra Götaland
Note

Open access funding provided by Örebro University. This study has received funding from Nyckelfonden, Örebro, Sweden (OLL-881491), Analytic Imaging Diagnostics Arena (AIDA), Linköping, Sweden (2104_Lidén) and Region Örebro län, Sweden (OLL-959996).The main funding body of The Swedish CArdioPulmonary bio-Image Study (SCAPIS) is the Swedish Heart and Lung Foundation. SCAPIS is also funded by the Knut and Alice Wallenberg Foundation, the Swedish Research Council and VINNOVA (Sweden’s Innovation Agency). In addition, the SCAPIS pilot received support from the Sahlgrenska Academy at University of Gothenburg and Region Västra Götaland.

Available from: 2023-08-10 Created: 2023-08-10 Last updated: 2024-04-09Bibliographically approved
Krauss, W., Janusz, F., Heydorn Lagerlöf, J., Lidén, M. & Thunberg, P. (2024). Radiomics from multisite MRI and clinical data to predict clinically significant prostate cancer. Acta Radiologica, 23(1), Article ID 103422.
Open this publication in new window or tab >>Radiomics from multisite MRI and clinical data to predict clinically significant prostate cancer
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2024 (English)In: Acta Radiologica, ISSN 0284-1851, E-ISSN 1600-0455, Vol. 23, no 1, article id 103422Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Magnetic resonance imaging (MRI) is useful in the diagnosis of clinically significant prostate cancer (csPCa). MRI-derived radiomics may support the diagnosis of csPCa. PURPOSE: To investigate whether adding radiomics from biparametric MRI to predictive models based on clinical and MRI parameters improves the prediction of csPCa in a multisite-multivendor setting.

MATERIAL AND METHODS: Clinical information (PSA, PSA density, prostate volume, and age), MRI reviews (PI-RADS 2.1), and radiomics (histogram and texture features) were retrieved from prospectively included patients examined at different radiology departments and with different MRI systems, followed by MRI-ultrasound fusion guided biopsies of lesions PI-RADS 3-5. Predictive logistic regression models of csPCa (Gleason score ≥7) for the peripheral (PZ) and transition zone (TZ), including clinical data and PI-RADS only, and combined with radiomics, were built and compared using receiver operating characteristic (ROC) curves.

RESULTS: In total, 456 lesions in 350 patients were analyzed. In PZ and TZ, PI-RADS 4-5 and PSA density, and age in PZ, were independent predictors of csPCa in models without radiomics. In models including radiomics, PI-RADS 4-5, PSA density, age, and ADC energy were independent predictors in PZ, and PI-RADS 5, PSA density and ADC mean in TZ. Comparison of areas under the ROC curve (AUC) for the models without radiomics (PZ: AUC = 0.82, TZ: AUC = 0.80) versus with radiomics (PZ: AUC = 0.82, TZ: AUC = 0.82) showed no significant differences (PZ: P = 0.366; TZ: P = 0.171).

CONCLUSION: PSA density and PI-RADS are potent predictors of csPCa. Radiomics do not add significant information to our multisite-multivendor dataset.

Place, publisher, year, edition, pages
Sage Publications, 2024
Keywords
PI-RADS, magnetic resonance imaging, multisite-multivendor, prostate cancer, radiomics
National Category
Urology and Nephrology Radiology, Nuclear Medicine and Medical Imaging Cancer and Oncology
Identifiers
urn:nbn:se:oru:diva-110453 (URN)10.1177/02841851231216555 (DOI)001127589000001 ()38115809 (PubMedID)2-s2.0-85180205504 (Scopus ID)
Funder
Region Örebro County
Available from: 2023-12-20 Created: 2023-12-20 Last updated: 2024-04-11Bibliographically approved
Thunberg, P., Wastensson, G., Lidén, G., Adjeiwaah, M., Tellman, J., Bergström, B., . . . Lundberg, P. (2024). Welding techniques and manganese concentrations in blood and brain: Results from the WELDFUMES study. Neurotoxicology, 105, 121-130
Open this publication in new window or tab >>Welding techniques and manganese concentrations in blood and brain: Results from the WELDFUMES study
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2024 (English)In: Neurotoxicology, ISSN 0161-813X, E-ISSN 1872-9711, Vol. 105, p. 121-130Article in journal (Refereed) Published
Abstract [en]

This study used whole-brain mapping to investigate the effect of different welding processes on manganese (Mn) accumulation in the brain. Exposure measurements were performed at the welders' workplaces about 3 weeks before a magnetic resonance imaging (MRI) examination. The welders were categorized into three main groups based on welding method, and the T1-relaxation rate (R1) was measured using quantitative MRI (qMRI). Welders using shielded metal arc welding (SMAW) were found to have lower accumulations of total Mn in clusters encompassing white matter, thalamus, putamen, pallidum, and substantia nigra compared with welders using inert gas tungsten arc welding (GTAW) or continuous consumable electrode arc welding (CCEAW). A positive correlation was found between Mn in red blood cells (Mn-RBC) and R1 in a region encompassing pre-and post-central gyri. The results of this study show that the accumulation of free, bound, or compartmentalized Mn ions in the brain differed depending on the welding method used. These differences were predominately located in the basal ganglia but were also found in regions encompassing white matter. The level of Mn-RBC was correlated to the deposition of Mn in the left primary somatosensory and motor cortex and may therefore be linked to neurological and neurobehavioral symptoms.

Place, publisher, year, edition, pages
Elsevier, 2024
Keywords
Manganese, R1-relaxation rate, Welding
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:oru:diva-116395 (URN)10.1016/j.neuro.2024.09.005 (DOI)001327210500001 ()39326638 (PubMedID)2-s2.0-85204890338 (Scopus ID)
Funder
Forte, Swedish Research Council for Health, Working Life and Welfare, 2014–0993
Available from: 2024-09-30 Created: 2024-09-30 Last updated: 2024-10-16Bibliographically approved
Humble, M. B., Eklund, D., Fresnais, D., Hylén, U., Sigra, S., Thunberg, P. & Bejerot, S. (2023). Rituximab for treatment-resistant schizophrenia and/or obsessive-compulsive disorder (OCD): functional connectivity and cytokines associated with symptomatic improvements. Paper presented at 31st European Congress of Psychiatry (EPA 2023), Paris, France, March 25-28, 2023. European psychiatry, 66(Suppl. 1), S629-S629, Article ID EPP1035.
Open this publication in new window or tab >>Rituximab for treatment-resistant schizophrenia and/or obsessive-compulsive disorder (OCD): functional connectivity and cytokines associated with symptomatic improvements
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2023 (English)In: European psychiatry, ISSN 0924-9338, E-ISSN 1778-3585, Vol. 66, no Suppl. 1, p. S629-S629, article id EPP1035Article in journal, Meeting abstract (Other academic) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Cambridge University Press, 2023
National Category
Psychiatry
Identifiers
urn:nbn:se:oru:diva-109391 (URN)10.1192/j.eurpsy.2023.1309 (DOI)001060676601588 ()
Conference
31st European Congress of Psychiatry (EPA 2023), Paris, France, March 25-28, 2023
Available from: 2023-10-25 Created: 2023-10-25 Last updated: 2024-03-18Bibliographically approved
Rode, J., Runnamo, R., Thunberg, P. & Msghina, M. (2023). Salience and hedonic experience as predictors of central stimulant treatment response in ADHD: A resting state fMRI study. Journal of Psychiatric Research, 163, 378-385
Open this publication in new window or tab >>Salience and hedonic experience as predictors of central stimulant treatment response in ADHD: A resting state fMRI study
2023 (English)In: Journal of Psychiatric Research, ISSN 0022-3956, E-ISSN 1879-1379, Vol. 163, p. 378-385Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Roughly 20-30% of patients with Attention-deficit/hyperactivity disorder (ADHD) fail to respond to central stimulant (CS) medication. Genetic, neuroimaging, biochemical and behavioral biomarkers for CS response have been investigated, but currently there are no biomarkers available for clinical use that help identify CS responders and non-responders.

METHODS: In the present paper, we studied if incentive salience and hedonic experience evaluated after a single-dose CS medication could predict response and non-response to CS medication. We used a bipolar visual analogue 'wanting' and 'liking' scale to gauge incentive salience and hedonic experience in 25 healthy controls (HC) and 29 ADHD patients. HC received 30 mg methylphenidate (MPH) and ADHD patients received either MPH or lisdexamphetamine (LDX) as selected by their clinician, with dosage individually determined for optimal effect. Clinician-evaluated global impression - severity (CGI-S) and improvement (CGI-I) and patient-evaluated improvement (PGI-I) were used to assess response to CS medication. Resting state functional magnetic resonance imaging (fMRI) was conducted before and after single-dose CS to correlate wanting and liking scores to changes in functional connectivity.

RESULTS: Roughly 20% of the ADHD patients were CS non-responders (5 of 29). CS responders had significantly higher incentive salience and hedonic experience scores compared to healthy controls and CS non-responders. Resting state fMRI showed that wanting scores were significantly associated to changes in functional connectivity in ventral striatum including nucleus accumbens.

CONCLUSION: Incentive salience and hedonic experience evaluated after a single-dose CS medication segregate CS responders and non-responders, with corresponding neuroimaging biomarkers in the brain reward system.

Place, publisher, year, edition, pages
Elsevier, 2023
Keywords
Attention-deficit/hyperactivity disorder, Central stimulant treatment, Incentive salience, Pharmacological challenge, Resting state, Treatment prediction
National Category
Psychiatry
Identifiers
urn:nbn:se:oru:diva-106174 (URN)10.1016/j.jpsychires.2023.05.073 (DOI)001013035000001 ()37269772 (PubMedID)2-s2.0-85160538869 (Scopus ID)
Funder
Nyckelfonden, 93542Region Örebro County, OLL-787911
Available from: 2023-06-05 Created: 2023-06-05 Last updated: 2024-01-02Bibliographically approved
Bejerot, S., Eklund, D., Hesser, H., Hietala, M. A., Kariis, T., Lange, N., . . . Humble, M. B. (2023). Study protocol for a randomized controlled trial with rituximab for psychotic disorder in adults (RCT-Rits). BMC Psychiatry, 23(1), Article ID 771.
Open this publication in new window or tab >>Study protocol for a randomized controlled trial with rituximab for psychotic disorder in adults (RCT-Rits)
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2023 (English)In: BMC Psychiatry, E-ISSN 1471-244X, Vol. 23, no 1, article id 771Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
BioMed Central (BMC), 2023
Keywords
Clinical trials, Immunology, Inflammation, Magnetic resonance imaging, Monoclonal antibodies, Schizophrenia & psychotic disorders
National Category
Psychiatry
Identifiers
urn:nbn:se:oru:diva-109377 (URN)10.1186/s12888-023-05250-5 (DOI)001095789000002 ()37872497 (PubMedID)2-s2.0-85174826025 (Scopus ID)
Funder
Örebro UniversitySwedish Research Council, 2022-00288The Swedish Brain Foundation, FO2022-0073Torsten Söderbergs stiftelse, MT4/22
Note

Study protocol

Available from: 2023-10-24 Created: 2023-10-24 Last updated: 2025-01-20Bibliographically approved
Rode, J., Edebol Carlman, H. M. T., König, J., Hutchinson, A., Thunberg, P., Persson, J. & Brummer, R. J. (2022). Multi-Strain Probiotic Mixture Affects Brain Morphology and Resting State Brain Function in Healthy Subjects: An RCT. Cells, 11(18), Article ID 2922.
Open this publication in new window or tab >>Multi-Strain Probiotic Mixture Affects Brain Morphology and Resting State Brain Function in Healthy Subjects: An RCT
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2022 (English)In: Cells, E-ISSN 2073-4409, Vol. 11, no 18, article id 2922Article in journal (Refereed) Published
Abstract [en]

Probiotics can alter brain function via the gut-brain axis. We investigated the effect of a probiotic mixture containing Bifidobacterium longum, Lactobacillus helveticus and Lactiplantibacillus plantarum. In a randomized, placebo-controlled, double-blinded crossover design, 22 healthy subjects (6 m/16 f; 24.2 ± 3.4 years) underwent four-week intervention periods with probiotics and placebo, separated by a four-week washout period. Voxel-based morphometry indicated that the probiotic intervention affected the gray matter volume of a cluster covering the left supramarginal gyrus and superior parietal lobule (p &lt; 0.0001), two regions that were also among those with an altered resting state functional connectivity. Probiotic intervention resulted in significant (FDR &lt; 0.05) functional connectivity changes between regions within the default mode, salience, frontoparietal as well as the language network and several regions located outside these networks. Psychological symptoms trended towards improvement after probiotic intervention, i.e., the total score of the Hospital Anxiety and Depression Scale (p = 0.056) and its depression sub-score (p = 0.093), as well as sleep patterns (p = 0.058). The probiotic intervention evoked distinct changes in brain morphology and resting state brain function alongside slight improvements of psycho(bio)logical markers of the gut-brain axis. The combination of those parameters may provide new insights into the modes of action by which gut microbiota can affect gut-brain communication and hence brain function.

Place, publisher, year, edition, pages
MDPI, 2022
Keywords
CO2 inhalation challenge, autonomic nervous system, brain-derived neurotrophic factor (BDNF), cortisol awakening response, gut microbiota, mental health, resting state functional connectivity, serotonin, sleep quality, structural changes
National Category
Neurology
Identifiers
urn:nbn:se:oru:diva-101446 (URN)10.3390/cells11182922 (DOI)000858164900001 ()36139496 (PubMedID)2-s2.0-85138356660 (Scopus ID)
Note

Funding agencies:

Global Medical Innovation

Pfizer Consumer Healthcare

General Electric 20150081

Available from: 2022-09-24 Created: 2022-09-24 Last updated: 2022-10-05Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-8351-3367

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