Search

Abstract A significant proportion of the personal and economic burden of schizophrenia can be attributed to the late diagnosis or misdiagnosis of the disorder. A novel, objective diagnostic approaches could facilitate the early detection and treatment of schizophrenia and improve patient outcomes. In the present study, we aimed to identify robust schizophrenia-specific blood biomarkers, with the goal of developing an accurate diagnostic model. The levels of selected serum and peripheral blood mononuclear cell (PBMC) markers relevant to metabolic and immune function were measured in healthy controls (n = 26) and recent-onset schizophrenia patients (n = 36) using multiplexed immunoassays and flow cytometry. Analysis of covariance revealed significant upregulation of insulin receptor (IR) and fatty acid translocase (CD36) levels in T helper cells (F = 10.75, P = 0.002, Q = 0.024 and F = 21.58, P = 2.8 × 10−5, Q = 0.0004, respectively), as well as downregulation of glucose transporter 1 (GLUT1) expression in monocytes (F = 21.46, P = 2.9 × 10−5, Q = 0.0004). The most robust predictors, monocyte GLUT1 and T helper cell CD36, were used to develop a diagnostic model, which showed a leave-one-out cross-validated area under the receiver operating characteristic curve (AUC) of 0.78 (95% CI: 0.66–0.92). The diagnostic model was validated in two independent datasets. The model was able to distinguish first-onset, drug-naïve schizophrenia patients (n = 34) from healthy controls (n = 39) with an AUC of 0.75 (95% CI: 0.64–0.86), and also differentiated schizophrenia patients (n = 22) from patients with other neuropsychiatric conditions, including bipolar disorder, major depressive disorder and autism spectrum disorder (n = 68), with an AUC of 0.83 (95% CI: 0.75–0.92). These findings indicate that PBMC-derived biomarkers have the potential to support an accurate and objective differential diagnosis of schizophrenia.

Abstract Introduction The barrier function of the gut is important for many organs and systems, including the brain. If gut permeability increases, bacterial fragments may enter the circulation, giving rise to increased systemic inflammation. Increases in bacterial translocation are reflected in higher values of blood markers, including lipopolysaccharide binding protein (LBP) and soluble cluster of differentiation 14 (sCD14). Some pioneer studies showed a negative association between bacterial translocation markers and brain volumes, but this association remains scarcely investigated. We investigate the effect of bacterial translocation on brain volumes and cognition in both healthy controls and patients with a schizophrenia spectrum disorder (SSD). Materials and methods Healthy controls (n = 39) and SSD patients (n = 72) underwent an MRI‐scan, venipuncture and cognition assessments. We investigated associations between LBP and sCD14 and brain volumes (intracranial volume, total brain volume, and hippocampal volume) using linear regression. We then associated LBP and sCD14 to cognitive function using a mediation analysis, with intracranial volume as mediator. Results Healthy controls showed a negative association between hippocampal volume and LBP (b = –0.11, p = .04), and intracranial volume and sCD14 (b = –0.25, p = .07). Both markers were indirectly associated with lower cognitive functioning in healthy controls (LBP: b = –0.071, p = .028; sCD14: b = –0.213, p = .052), mediated by low intracranial volume. In the SSD patients, these associations were markedly less present. Conclusion These findings extend earlier studies suggesting that increased bacterial translocation may negatively affect brain volume, which indirectly impacts cognition, even in this young healthy group. If replicated, this finding stresses the importance of a healthy gut for the development and optimal functioning of the brain. Absence of these associations in the SSD group may indicate that other factors such as allostatic load, chronic medication use and interrupted educational carrier had larger impact and attenuated the relative contribution of bacterial translocation.

Immune dysregulation has been reported in schizophrenia spectrum disorders (SSD). In the past decade, several trials using anti-inflammatory agents for treatment of SSD have been completed, with so far limited success. One such anti-inflammatory agent used is simvastatin. A recent, large-scale, randomized controlled trial with simvastatin augmentation failed to show improvement in the predefined primary outcome. However, baseline inflammatory profiles were not taken into account. Here we employed a data-driven clustering approach to investigate whether patients with an inflammatory monocyte gene signature respond better to add-on simvastatin treatment than those without such a signature, over a treatment period of 2 years. In 61 patients (60 randomized, 1:1 placebo:simvastatin) and healthy controls, a previously validated monocyte gene expression signature was assessed using quantitative polymerase chain reaction. Resulting delta cycle threshold values were used to identify patient clusters. Two major patient clusters with either up- or downregulated pro-inflammatory factors were detected. Linear mixed models showed a significant three-way interaction between the inflammatory cluster, treatment, and time for psychotic symptoms. Only patients treated with simvastatin who were in the inflammatory group, showed a consistent improvement: symptom severity gradually decreased after 3 months and reached significance after 12 and 24 months compared to baseline (p.adj

Abstract Background The symptom severity of a substantial group of schizophrenia patients (30–40%) does not improve through pharmacotherapy with antipsychotic medication, indicating a clear need for new treatment options to improve schizophrenia outcome. Meta-analyses, genetic studies, randomized controlled trials, and post-mortem studies suggest that immune dysregulation plays a role in the pathophysiology of schizophrenia. Some anti-inflammatory drugs have shown beneficial effects on the symptom severity of schizophrenia patients. Corticosteroids are effective in various chronic inflammatory and autoimmune disorders. Prednisolone, a potent glucocorticosteroid, has minor mineral-corticosteroid potencies and can adequately pass the blood–brain barrier and its side effects and safety profile are well known. Therefore, the effect of prednisolone can be studied as a proof of concept for immune modulation as a treatment for schizophrenia. Methods/design In total, 90 subjects aged 18–70 years and diagnosed with schizophrenia, schizoaffective disorder, or schizophreniform disorder (Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) 295.x) or psychosis not otherwise specified (NOS; 298.9) will be included. The time interval between the onset of psychosis and study entry should not exceed 7 years. Patients will be randomized 1:1 to either prednisolone or placebo daily for a period of 6 weeks in addition to a stable dose of antipsychotic medication. Study medication will be initiated at 40 mg for 3 days, after which it will be tapered down within 6 weeks after initiation, following inflammatory bowel diseases treatment guidelines. Primary outcome is change in symptom severity, expressed as change in total score on the Positive and Negative Symptom Scale (PANSS) from baseline to end of treatment. Cognitive functioning (measured through the Brief Assessment of Cognition in Schizophrenia (BACS)) and change in Global Assessment Functioning (GAF) and depressive symptoms as measured with the Calgary Depression Scale for Schizophrenia (CDS) will be assessed, in addition to various immunological biomarkers. Secondary outcomes are a 4- and 6-month follow-up assessment of PANSS, BACS, and GAF scores and immunological biomarkers. Additionally, a subgroup of patients will be included in the magnetic resonance imaging (MRI) part of the study where MR spectroscopy and structural, functional, and diffusion MRI will be conducted. Discussion It is expected that prednisolone addition to current antipsychotic medication use will reduce symptom severity and will improve cognition when compared to placebo. Trial registration ClinicalTrials.gov , NCT02949232 and NCT03340909 . Registered 31 October 2016 and 14 November 2017. EudraCT-number 2014–000520-14 and 2017–000163-32.

Abstract Background Antipsychotic medication is effective for symptomatic treatment in schizophrenia-spectrum disorders. After symptom remission, continuation of antipsychotic treatment is associated with lower relapse rates and lower symptom severity compared to dose reduction/discontinuation. Therefore, most guidelines recommend continuation of treatment with antipsychotic medication for at least 1 year. Recently, however, these guidelines have been questioned as one study has shown that more patients achieved long-term functional remission in an early discontinuation condition—a finding that was not replicated in another recently published long-term study. Methods/design The HAMLETT (Handling Antipsychotic Medication Long-term Evaluation of Targeted Treatment) study is a multicenter pragmatic single-blind randomized controlled trial in two parallel conditions (1:1) investigating the effects of continuation versus dose-reduction/discontinuation of antipsychotic medication after remission of a first episode of psychosis (FEP) on personal and social functioning, psychotic symptom severity, and health-related quality of life. In total 512 participants will be included, aged between 16 and 60 years, in symptomatic remission from a FEP for 3–6 months, and for whom psychosis was not associated with severe or life-threatening self-harm or violence. Recruitment will take place at 24 Dutch sites. Patients are randomized (1:1) to: continuation of antipsychotic medication until at least 1 year after remission (original dose allowing a maximum reduction of 25%, or another antipsychotic drug in similar dose range); or gradual dose reduction till eventual discontinuation of antipsychotics according to a tapering schedule. If signs of relapse occur in this arm, medication dose can be increased again. Measurements are conducted at baseline, at 3, and 6 months post-baseline, and yearly during a follow-up period of 4 years. Discussion The HAMLETT study will offer evidence to guide patients and clinicians regarding questions concerning optimal treatment duration and when to taper off medication after remission of a FEP. Moreover, it may provide patient characteristics associated with safe dose reduction with a minimal risk of relapse. Trial status Protocol version 1.3, October 2018. The study is active and currently recruiting patients (since September 2017), with the first 200 participants by the end of 2019. We anticipate completing recruitment in 2022 and final assessments (including follow-up 3.5 years after phase one) in 2026. Trial registration European Clinical Trials Database, EudraCT number 2017-002406-12. Registered 7 June 2017.

Introduction: Building upon the comorbidity between atopy and schizophrenia, we conducted a large cross-sectional, observational population-based study to examine if such associations also exist between atopic disorders (eczema, allergic rhinitis, and asthma) and nonclinical psychotic experiences.Methods: We examined psychotic experiences in a Dutch population sample through an online survey (≥14 years of age). Participants filled out the Questionnaire for Psychotic Experiences, together with questions screening for atopic disorders (eczema, allergic rhinitis, and asthma). Prevalence rates were calculated; binary logistic regression was used to determine odds ratios (ORs) (age, gender, and years of education as covariates).Results: We included 6,479 participants. Individuals diagnosed with one or more atopic disorders had an increased risk of psychotic experiences as compared with controls (OR = 1.26). Analysis of individual symptoms revealed an OR of 1.27 for hallucinations, whereas delusions only showed a trend. With each additional atopic disorder, the risk of psychotic experiences increased. This was also observed for hallucinations alone but not for delusions alone. Atopy was associated with hallucinations across all modalities (OR ranging from 1.19 to 1.40). These results did not appear to be driven specifically by any one of the atopic disorders.Conclusion: In the largest population sample of adolescents and adults to date, we found that atopic disorders (asthma, eczema, and allergic rhinitis) increase the risk of psychotic experiences, in a dose–response fashion. These results provide further support for the role of immunological components in the predisposition for psychosis and can serve as a base for further research.

Background/objectives: Negative symptoms in schizophrenia spectrum disorders are related to impaired social functioning and lower quality of life, making accurate assessment important. To date, most tools for assessing negative symptoms are observational, which can be influenced by the raters' experience and opinion. Self-rating scales, like the Self-Evaluation of Negative Symptoms (SNS), could complement observer ratings by adding information from the patient's perspective. Here, we aim to evaluate the psychometric properties of the Dutch translation of the SNS and the relationship between the SNS and functional outcomes., Methods: The SNS was added to the Pharmacotherapy Monitoring Outcome Survey (PHAMOUS)-protocol for adults with a DSM-5 classification of a disorder in the psychosis spectrum. Internal consistency was assessed by Cronbach's alpha. Confirmatory factor analysis (CFA) was used to evaluate the construct validity of the five subscales of the SNS. Correlational analyses were performed between the SNS and the Positive and Negative Syndrome Scale (PANSS), the Health of Nation Outcomes Scales (HoNOS), the Global Assessment of Functioning (GAF), Functional Remission tool (FR) and the Manchester Short Assessment of Quality of Life (ManSA)., Results: A total of 247 patients participated in this study. Internal consistency was good (α = 0.87). CFA confirmed the five-factor structure of the SNS. The SNS was significantly correlated (all p < 0.001) with the PANSS positive (r = 0.31), PANSS negative (r = 0.33), HoNOS (r = 0.37), FR (r = 0.27) and the ManSA (r = -0.40)., Conclusions: The Dutch SNS shows good psychometric properties and is related to functional outcomes and quality of life. The SNS can be valuable in complementing current observational-based instruments, and future research may investigate whether the SNS can be used as a standalone measurement tool for the assessment of negative symptoms.

Negative symptoms can be an integral part of schizophrenia spectrum pathology and can be secondary to other psychotic symptoms or caused by antipsychotic medication. As antipsychotic drugs differ in their affinity to dopamine receptors and some antipsychotics have partial agonistic effects, antipsychotic drugs are expected to vary in their ability to cause negative symptoms. The association between negative symptoms and antipsychotic medication divided into partial agonists, or antagonists with high or low D 2 affinity was assessed in 310 remitted first episode psychosis (FEP) patients. Severity of negative symptoms was assessed with the Comprehensive Assessment of Symptoms and History, and the Positive and Negative Syndrome Scale. Linear regression analyses were performed while controlling for differences in clinical and sociodemographic characteristics between the groups using inverse probability of treatment weighting. Patients using partial agonists (n = 78) showed fewer negative symptoms compared to those using high affinity antagonists (n = 84). Patients using partial agonists displayed less severe negative symptoms compared to those using low affinity antagonists (n = 148) at a trend level (p = 0.051). Negative symptom severity was higher in patients who had higher antipsychotic doses. In remitted FEP patients, we observed that the use of antipsychotic medication classified as partial agonists was associated with lower severity of negative symptoms, while the use of antagonists with high D 2 affinity was associated with more severe negative symptoms., Competing Interests: Declaration of competing interest F.B., B.W., L.W., S.K., S.G., W.V., N.B., L.H., M.B. report no financial relationships with commercial interest. I.S. participates in a trial from Boehringer-Ingelheim, has received speakers' fee from Otsuka, and a charity grant from Janssen., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Hypothesis: Throughout the life stages of women with schizophrenia-spectrum disorders (SSD), lower estrogen levels are associated with more severe disease course. At perimenopause in the mid-forties, estrogen levels decline to remain persistently low after menopause. This period is hypothesized to increase relapse risk and reduce antipsychotic effectiveness in preventing relapse., Study Design: The cohort of persons with schizophrenia/schizoaffective disorder was identified from Finnish nationwide registers (N = 61 889) and stratified by sex and age <45 vs. ≥45 years. Hospitalizations for psychosis were defined per 5-year age group during the follow-up 1996-2017. Risk of psychosis hospitalization (Adjusted Hazard Ratio, aHR) was assessed using within-individual design, by comparing antipsychotic monotherapy use to nonuse periods in the same individuals for seven dose categories in defined daily doses (DDDs/day)., Results: Starting at age 45-50, women were consistently more often hospitalized for psychosis than their male peers. Women ≥45 had significantly higher aHRs than women <45 at antipsychotic monotherapy >0.6 DDDs/day, and than men at >1.1 DDDs/day. This female-specific age-dependent decrease in effectiveness was present for clozapine doses >0.6 DDDs/day, olanzapine doses >1.4 DDDs/day, and for specific doses of quetiapine (0.9-1.1 DDDs/day) and risperidone (0.6-0.9 DDDs/day)., Conclusions: While younger women have a lower risk of relapse and generally need a lower antipsychotic dose to prevent rehospitalization than men, antipsychotic effectiveness declines in women after the age of 45. Starting in mid-forties, older women with SSD should be regarded as a vulnerable group that deserve special attention., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)