Upregulation of sICAM-1 and sVCAM-1 Levels in the Cerebrospinal Fluid of Patients with Schizophrenia Spectrum Disorders

Upregulation of sICAM-1 and sVCAM-1 Levels in the Cerebrospinal Fluid of Patients with Schizophrenia Spectrum Disorders | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Upregulation of sICAM-1 and sVCAM-1 Levels in the Cerebrospinal Fluid of Patients with Schizophrenia Spectrum Disorders Sophie Meixensberger, Hanna Kuzior, Bernd Fiebich, Patrick Süß, and 11 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-121960/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 22 Jun, 2021 Read the published version in Diagnostics → Version 1 posted You are reading this latest preprint version Abstract Introduction Immunological explanatory approaches are becoming increasingly important in schizophrenia research. In this context, the function of the blood–brain barrier (BBB) and the blood–cerebrospinal fluid (CSF) barrier (BCSFB) play an essential role. Different adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), are key elements in sustaining the integrity of the BBB and BCSFB. The objectives of this study were (1) to compare the levels of different cell adhesion molecules in the CSF of patients with schizophrenia spectrum disorders to those of patients with unipolar depression and (2) to analyze their association with the established markers of the BBB/BCSFB function (total protein and albumin quotient [AQ]). Patients and methods A total of 40 patients with schizophrenia spectrum disorder and 39 age- and sex-matched control patients with unipolar depression were analyzed. The levels of soluble ICAM-1 (s-ICAM-1), soluble VCAM-1 (s-VCAM-1), and plasminogen activator inhibitor 1 (PAI-1) in the CSF were measured using a magnetic bead multiplexing immunoassay. Results The levels of sICAM-1 (p<0.001), sVCAM-1 (p<0.001), and PAI-1 (p<0.001) in the CSF were significantly higher in patients with schizophrenia spectrum disorder than in patients with unipolar depression. Correlation analyses revealed a significant correlation of protein concentrations with sVCAM-1 levels (r=0.505, p=0.001) and of AQs with the sVCAM-1 (r=0.583, p<0.001) and PAI-1 (r=0.337, p=0.033) levels in patients with schizophrenia. Limitation The significance of the study is limited by the retrospective research design and by the absence of a healthy control group. The assay used was not previously established for the measurement of CSF. Discussion Results revealed that sICAM-1 and sVCAM-1 levels in the CSF are higher in patients with schizophrenia spectrum disorder than in patients with depression. These circulating signaling molecules may indicate endothelial dysfunction causing impaired BBB/BCSFB function in patients with schizophrenia spectrum disorders. Consistent with this view, a highly significant correlation of sVCAM-1 with CSF protein and AQs was detected. Upregulation of these cell adhesion molecules might be indicative of a proinflammatory immune response underlying the BBB/BCSFB disturbance in a subgroup of patients with schizophrenia spectrum disorders. Further translational and controlled studies on the role of different cell adhesion molecules in schizophrenia are needed. Psychiatry ICAM-1 VCAM-1 schizophrenia depression neuroinflammation blood–brain barrier cerebrospinal fluid Figures Figure 1 1. Introduction Immunological explanatory approaches are becoming increasingly important in schizophrenia research (Pollak et al., 2020). Schizophrenia spectrum disorders were interpreted by several authors as complex neuropsychiatric disorders involving an activated inflammatory response leading to mild neuroinflammation (Bechter, 2013; Muller, 2019; Müller et al., 2013; Nguyen et al., 2018; Stefanovic et al., 2016). In this context, the functions of the blood–brain barrier (BBB) and the blood–cerebrospinal fluid (CSF) barrier (BCSFB) play a central role (Pollak et al., 2018), and a number of clinical studies showed alterations in biomarkers associated with the BBB/BCSFB (Endres et al., 2020; Endres et al., 2015; Najjar et al., 2017; Najjar et al., 2013; Orlovska-Waast et al., 2019). The central nervous system (CNS) is surrounded by the dynamic and metabolically active CSF and is separated from the peripheral circulation by several barriers, the most prominent are the BBB and the BCSFB (Banks et al., 2010; Deisenhammer et al., 2006; Tumani et al., 2017; Wildemann et al., 2010). The BBB/BCSFB form the primary interface that exerts key functions in brain homeostasis and immune protection (Banks et al., 2010; Najjar et al., 2017). One of the most notable components responsible for barrier integrity are the brain capillary endothelial cells that sustain a paracellular pathway with a highly selective permeability mediated by selective transport vesicles and tight junctions (Carvey et al., 2009; Pollak et al., 2018; Serlin et al., 2015). In this cerebral microvascular endothelium, different intercellular adhesion molecules, particularly intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), are expressed under chronic inflammatory conditions (Kong et al., 2018; Müller, 2019). Endothelial cells are not only a passive barrier but also immunologically active themselves. For example, they can produce chemokines (Blank et al., 2016), and endothelial VCAM-1 is associated with age- and inflammation-induced microglia activation, impaired neurogenesis and cognitive deficits. These changes are diminished by antagonization of VCAM-1 and can occur even without disturbance of the BBB/BCSFB parameters or infiltration of immune cells (Yousef et al., 2019). Previous studies comparing patients with schizophrenia spectrum disorder and controls revealed contradictory findings on soluble ICAM-1 (sICAM-1) and soluble VCAM-1 (sVCAM-1) levels when obtained with different methods and samples, including serum, CSF, and postmortem CNS tissues, as summarized in Table 1 (Müller, 2019). The objective of this study was to conduct the first controlled CSF study that investigates cell adhesion molecules in patients with schizophrenia spectrum disorders and in a psychiatric control group. More specifically, we (1) compared the levels of different cell adhesion molecules in the CSF of patients with schizophrenia spectrum disorders to those of patients with unipolar depression and (2) we analyzed the association of these cell adhesion molecules with the established CSF markers of BBB/BCSFB function (i.e., total CSF protein and albumin quotient [AQ]). 2. Participants And Methods This study was part of a larger retrospective project that was approved by the local ethics committee (Faculty of Medicine, University of Freiburg, ethical vote no. 396/18). Lumbar punctures were performed after careful gathering of information and after obtaining written informed consent as part of clinical routine to rule out organic causes of psychiatric symptoms This study was carried out in accordance with relevant guidelines and regulations. 2.1 Study sample A total of 40 patients diagnosed with schizophrenia spectrum disorder and 39 patients diagnosed with unipolar depression were included in this study (for clinical and demographic details see tables 2 and 3). Based on the predominant clinical syndrome, patients were classified according to the criteria set by the International Statistical Classification of Diseases and Related Health Problems, 10th revision (ICD-10). In the schizophrenia cohort, 13 patients went through their first episode and 27 suffered from a chronic or recurrent manifestation, with chronic being defined as a period of more than two years. In the depression cohort, 12 patients suffered from their first episode and 27 patients were in a chronic or recurrent stage. All 39 patients in the depression cohort were diagnosed with a severe depressive episode. 2.2 Cerebrospinal fluid analysis and instrumental diagnostics The routine CSF analysis included the determination of white blood cell (WBC) count, protein concentration, AQ, immunoglobulin (Ig)G index, and oligoclonal bands (OCBs) according to an established methodology (c.f. Endres et al., 2015, 2020). The measurements were carried out in the CSF laboratory of the University Hospital Freiburg (https://www.uniklinik-freiburg.de/neurologie/klinik/diagnostische-einrichtungen/liquor-labor.html). Electroencephalography (EEG) and cerebral magnetic resonance imaging (MRI) were offered to all patients as part of the clinical routine work-up. 3. Measurement of cell-adhesions markers The adhesion molecules were quantified through a magnetic bead-based multiplex immunoassay by using a Human Adhesion Magnetic 6-Plex Panel (ThermoFisher, Waltham, MA); a MAGPIX® machine (ThermoFisher, Waltham, MA) was used to read and analyze the assay. The panel utilized to investigate sICAM-1, sVCAM-1, plasminogen activator inhibitor 1 (PAI-1), P-selectin, E-selectin, and platelet endothelial cell adhesion molecule-1 (PECAM) was used in accordance with the manufacturer’s specifications, with the exception of using undiluted CSF samples, as this panel was originally not established for CSF analysis. The reported values are corrected for the different dilution. To determine whether the calculated concentrations of the individual adhesion molecules were reliable, we investigated the mean fluorescent intensity after deduction of the blank value, which is known as the net median fluorescence intensity (NetMFI), as well as the number of magnetic beads measured per analyte per well (bead count; cf. Kuzior et al., 2020). In this study, all values with a NetMFI below the lowest standard of the standard curve of the respective cell adhesion molecule and all wells with a bead count below 20 were excluded (c.f. with Kuzior et al., 2020). Only the samples that were measurable (and therefore not below the detection level) for >50% of the analytes were analyzed. The adhesion molecule concentrations below the detection level were set to zero. 2.4 Data handling and statistical analyses Data was analyzed using the Statistical Package for the Social Sciences (SPSS), version 24 (IBM Corp., Armonk, NY). Group comparisons for categorical variables were conducted using the Pearson’s chi-squared test, whereas group comparisons for continuous variables were performed using two-sided independent sample t-tests. A Pearson correlation between CSF basic parameters (WBC count, protein concentration, AQ, and IgG index) and cell adhesion molecules (sICAM-1, sVCAM-1, and PAI-1) was separately performed for each group (schizophrenia and unipolar depression). A p-value of <0.05 was set to indicate statistical significance. No correction for multiple testing was performed given that an exploratory approach was implemented in this study. 3. Results 3.1 Sociodemographic data The sociodemographic data is summarized in Tables 2 and 3. The schizophrenia spectrum and depressive patient groups were matched for age (F=11.455, p=0.660) and sex (Chi 2 =0.141, p=0.707). 3.2 Cell adhesion molecules in the cerebrospinal fluid The cell adhesion molecules sICAM-1, sVCAM-1, and PAI-1 in the CSF were successfully measured. The other parameters could not be measured sufficiently. The levels of sICAM-1 (p<0.001), sVCAM-1 (p<0.001), and PAI-1 (p<0.001) in the CSF were significantly higher in the patients with schizophrenia spectrum disorder than in those with unipolar depression (Table 4). Subgroup analyses between patients with schizoaffective (N=11) and the other patients from the schizophrenia spectrum disorder group (N=29) had similar mean ages (F=0.213, p=0.345). Both groups did not differ in the concentrations of sICAM (F=0.042, p=0.541), sVCAM (F=3.029, p=0.054), and PAI (F=0.057, p=0.239). The sICAM-1, sVCAM-1, and PAI-1 levels in patients with first-episode schizophrenia spectrum disorder or depression did not significantly differ from those in patients with a chronic/recurrent state of the diseases (data not shown in detail). 3. Basic cerebrospinal fluid findings and instrumental diagnostics The routine findings for CSF diagnostics are presented in Table 5. Overall, no significant differences in WBC counts, protein concentration, AQs, IgG indices, and rate of OCBs were observed between the schizophrenia and depression groups. Also, the number of total abnormalities in MRI (in 63% of patients with schizophrenia-spectrum disorders and in 67% of patients with depression; Chi 2 =0.278, p=0.598) in the two groups did not differ significantly, although EEG pathologies occurred more frequently in the schizophrenia group (in 25%; versus in 5% of the patients with depression; Chi 2 =6.053, p=0.014). 3.4 Correlation analyses In the schizophrenia spectrum disorder cohort, the CSF total protein concentration correlated significantly with the sVCAM-1 levels (r=0.505, p=0.001), and the AQ correlated with the sVCAM-1 (r=0.583, p<0.001; see Figure 1) and PAI-1 levels (r=0.337, p=0.033). By contrast, the levels of the cell adhesion molecules were not significantly correlated with clinical features, including suicide attempts and the number of earlier inpatient stays. In the unipolar depression cohort, no significant correlations of sICAM-1, sVCAM-1, and PAI-1 levels with WBC count, CSF total protein, AQ, and IgG index were detected. Also, the levels of the adhesion molecules were not significantly correlated with clinical features, including suicide attempts and the number of earlier inpatient stays. 4. Discussion The results of this study revealed significantly elevated sICAM-1 and sVCAM-1 levels in patients suffering from schizophrenia spectrum disorders compared to patients with depressive disorders. Oriented to established CSF reference values (using ELISA-technique) of sICAM according to which CSF values < 300 pg/mL must be assumed in healthy controls, the values in depressed patients (Mean: 466.205 pg/ml) have been found to be already slightly increased and those in schizophreniform disorders were clearly elevated and on average four times above the established reference value (Mean: 1196 pg/ml) (for reference values see: https://07525720-0688-4380-840d-0a4af942fef7.filesusr.com/ugd/92c932_454e4d6908d94f64b3623b621179eade.pdf). An upregulation of these signaling molecules in the schizophrenia spectrum disorder cohort may firstly be indicative of neuroinflammatory processes followed by a proinflammatory immune response (Müller, 2019; Ramos et al., 2014). Second, the overexpression of the adhesion molecules may be related to an impairment of the BBB/BCSFB (Müller, 2019; Schwarz et al., 1998). Accordingly, the sVCAM-1 levels correlated with the AQ (which is considered the gold standard estimating the integrity of the BBB/BCSFB) in patients with schizophrenia spectrum disorders (Pollak et al., 2018; Reiber et al., 2001; Reiber et al., 2018; Tumani et al., 2017; Wildemann et al., 2010). 4.1 Integration of our findings into the context of the current research Increased sICAM-1 levels have been observed in multiple inflammatory and cell-mediated autoimmune disorders (Radu et al., 2020). The current findings of increased CSF levels of this molecule are consistent with the reported significant elevation of plasma sICAM-1 levels in patients with schizophrenia spectrum disorder (Cai et al., 2020; Stefanovic et al., 2016). Stefanovic et al. (2016) discerned increased sICAM-1 levels in patients at a late stage of the disease, whereas no difference between healthy controls and patients with schizophrenia spectrum disorder was found in the early disease stages. By contrast, decreased peripheral levels of sICAM-1 and sVCAM-1 have been reported in another cohort of patients with schizophrenia spectrum disorders (Schwarz et al., 2000). In the explanatory approach, these contradictory findings may be explained in the light of a dysfunctional neuroendocrine immune communication and a reduced immune response during the acute onset of schizophrenia, whereas an overexpression could be an indication of an immune activation during a prolonged course of the disease (Müller, 2019; Nguyen et al., 2018). Consistent with this view, 68% (27 out of 40) of the patients with schizophrenia in the present cohort suffered from a recurrent/chronic course of the disease. However, we were not able to detect significant differences that distinguish patients with the first episode from those with the recurrent/chronic stage. In the first, uncontrolled CSF study on cell adhesion molecules in schizophrenia, a significant correlation was found between sICAM-1 level and AQs (Schwarz et al., 1998); this finding could not be replicated in our data. However, a significant positive correlation between sVCAM-1 levels and AQs was discerned (see Figure 1). 4.2 Pathophysiological and clinical considerations An increase in circulating proinflammatory cytokines was determined in the context of multiple psychiatric disorders (Cai et al., 2020; Lawson et al., 2009; Nguyen et al., 2018). Different inflammatory mediators (e.g., TNFα, IL-1β, and IFNγ) induce the expression levels of ICAM-1 and VCAM-1 (Kong et al., 2018; Najjar et al., 2017; Najjar et al., 2013; Nguyen et al., 2018). ICAM-1 (CD54) is a transmembrane glycoprotein of approximately 100 kDa in size; it belongs to the immunoglobulin supergene family and it consists of five tandem immunoglobulin-like domains (Krönig et al., 2005; Lawson et al., 2009; Muller, 2019; Ramos et al., 2014). In the CNS, ICAM-1 is expressed most notably in microglial cells, astrocytes, and endothelial cells in the white and grey matter (Müller, 2019; Ramos et al., 2014). The ligations of ICAM-1 to the lymphocyte function-associated molecule 1 on the surface of endothelial cells and to the macrophage-associated antigen-1 receptors on leucocytes contribute to the immune cell infiltration during an inflammatory response (Cai et al., 2020; Krönig et al., 2005; Lawson et al., 2009). ICAM-1 enables the trans-endothelial migration of leukocytes to the site of inflammation and plays an important role in immunological synapse formation (the interaction between antigen-presenting cells and T cells), in lymphocyte activation, and in numerous cellular immune responses (Cai et al., 2020; Lawson et al., 2009; Muller, 2019; Radu et al., 2020; Ramos et al., 2014). Arising from alternative splicing and/or proteolytic cleavage of membrane-bound ICAM-1 messenger RNA, a circulating soluble form of ICAM-1 (sICAM-1) consisting of the complete extracellular domain can be found in serum and CSF (Krönig et al., 2005; Lawson et al., 2009; Ramos et al., 2014). The sICAM-1 and its membrane-bound form exert similar functions (Müller, 2019). The elevated levels of sICAM-1 in CSF—as demonstrated in the current study—or in serum may therefore be indicative of the upregulated state of the membrane-bound ICAM-1 in the brain (Müller, 2019). VCAM-1 (CD106) is a 90-kDa glycoprotein predominantly expressed in endothelial cells (Kong et al., 2018). VCAM-1 regulates the pathway involved in leukocyte recruitment and transendothelial migration during inflammation via the interaction of its domain 1 (and/or 4) with α4β1 integrin (Kong et al., 2018). In most cell types, the expression of leucocyte adhesion molecules, such as ICAM-1 and VCAM-1, is low under non-inflammatory conditions, whereas a state of overexpression was described in many pathological states, especially during chronic inflammatory processes (Kong et al., 2018; Muller, 2019; Pollak et al., 2018; Ramos et al., 2014). Given that ICAM-1 is widely expressed in tissues, ICAM-1 levels may thus indicate the general level of inflammation (Radu et al., 2020); by contrast, VCAM-1 seems to indicate the conditions of the cerebral endothelium and the dendritic cells more precisely and thus could be used to assess endothelial dysfunction (Radu et al., 2020). Correlations were observed between the elevated levels of ICAM-1 and the progression and severity of cancer, cardiovascular disease, and autoimmune disorders (Lawson et al., 2009; Muller, 2019) as well as between VCAM-1 and the progression of various immunological disorders, including rheumatoid arthritis, and cancer (Kong et al., 2018). In patients with schizophrenia spectrum disorders, the current study showed evidence of upregulated ICAM-1 and VCAM-1 levels, which may partially reflect the occurrence of leukocyte transendothelial recruitment and adhesion (Müller, 2019). The overexpression of ICAM-1 and VCAM-1 near the endothelial layer of the vessel wall impairs the vascular endothelial mitochondrial oxidative metabolism and directly destabilizes endothelial tight junctions (Kong et al., 2018; Najjar et al., 2017; Najjar et al., 2013; Nguyen et al., 2018). These processes increase the BBB/BCSFB permeability and allow the inappropriate migration of pro-inflammatory molecules into the brain parenchyma, enabling interactions between the innate and the peripheral adaptive immune systems in the brain (Bechmann et al., 2007; Carvey et al., 2009; Kong et al., 2018; Najjar et al., 2017). These theoretical considerations are supported by the correlation found between the sVCAM-1 levels and AQs in this study. In addition, it was earlier demonstrated that ICAM-1 and VCAM-1 can be elevated without an “open BBB/BCSFB”. In a review by Varatharaj and Galea (2017), disruptive and non-disruptive changes in the BBB were compared. The fact that there was no severe barrier disruption across the entire present cohort, but already high sICAM-1 and sVCAM-1 levels, could indicate that non-disruptive changes are underlying the pathological processes here. Therefore, the tight junctions would not be affected, but the endothelia would still let pass immune cells and/or secrete cytokines/chemokines. Thus, from a clinical perspective, sICAM-1 and sVCAM-1 could provide further information about the BBB/BCSFB function in addition to established CSF parameters such as AQ. 4.3 Limitations A limitation of the present study is its lack of a healthy control group. Especially with regard to CSF measurements. It is difficult to ethically justify lumbar punctures in a large group of healthy volunteers. Previously, we used a control group of patients with pseudotumor cerebri (e.g., Stich et al., 2015; Kuzior et al., 2020). In the current study, this approach was considered initially; unfortunately, we were unable to recruit a matched control group with an adequate sample size. However, we were able to use a clinical control group of patients with depressive disorders and established reference values. Patients with schizophrenia were routinely offered a lumbar puncture. In patients with depression, lumbar punctures were performed only in selected cases. These patients were not screened routinely and there probably is a selection bias towards severely depressed patients. In addition, the multiplexing immunoassay used was originally not established for CSF measurements, and its use may possibly have led to methodical inaccuracies and difficulties. However, most other methodological approaches have so far only been established for blood. Because CSF analysis was performed as part of clinical routine diagnostic work-up, the processes involved in sample processing were not completely standardized. The samples first underwent routine testing before being frozen at −80 °C. In future studies, samples should be processed directly according to established and pre-defined standard operating procedures. The influence of other possible contributing factors, including psychotropic medication or multiple vascular risk factors (Mantere et al., 2019; Muller, 2019; Nguyen et al., 2018), remains unclear and needs to be considered. In addition, we were not able to examine serum samples of the patients. This would have been helpful for the overall interpretation and comparison with the preliminary studies, which mostly only examined serum material. Finally, it is important to keep in mind that an overexpression of ICAM-1 is observed in a wide range of diseases and inflammation, even in depressive disorders; therefore, the present findings in patients with schizophrenia spectrum disorder probably do not reflect disease-specific processes (Müller, 2019). Due to the limitations mentioned above, the present results are to be considered preliminary and warrant replication in future studies. 5. Conclusions The schizophrenia spectrum disorder pathophysiology may involve an altered immune response and a disturbed communication between the CNS and the immune system due to an impaired BBB/BCSFB. The present results indicate that the circulating immune signaling molecules sICAM-1 and sVCAM-1 might play a relevant role in this context. Further translational, prospective, and controlled studies in this novel psychoneuroimmunological field of research are needed. 6. Declarations Disclosure statement: SMe: None. HK: None. BLF: None. PS: None. KR: None. BB: Received travel grants and/or training expenses from Bayer Vital GmbH, Ipsen Pharma GmbH, Norvartis, Biogen GmbH and Genzyme, as well as lecture fees from Ipsen Pharma GmbH, Alexion Pharma GmbH, Merck, Sanofi Genzyme and Roche. KN: None. DD: None. MAS: None. MM: None. SMa: None. KB: None. KD: Steering Committee Neurosciences, Janssen. LTvE: Advisory boards, lectures, or travel grants within the last three years: Roche, Eli Lilly, Janssen-Cilag, Novartis, Shire, UCB, GSK, Servier, Janssen and Cyberonics. DE: None. Authors’ contributions: SMe, BLF, HK, LTvE and DE created the study design. BLF, KD, DE and LTvE supervised the study. HK and BLF were responsible for laboratory measurements. BB performed CSF basic analyses. SMe and SMa performed the statistical analyses. SMe wrote the paper and performed the data search. DE critically revised the manuscript. HK, KR, PS, KN, DD, MAS, MM, KB, KD, and LTvE supported the interpretation and revised the manuscript further. All authors were critically involved in the theoretical discussion and composition of the manuscript. All authors read and approved the final version of the manuscript. Acknowledgement: DE was funded by the Berta-Ottenstein-Programme for Advanced Clinician Scientists, Faculty of Medicine, University of Freiburg. PS is a member of the research training group GRK2162 funded by the DFG (270949263/GRK2162) and is supported by the University Hospital Erlangen (ELAN project P059, IZKF clinician scientist program) Funding: The article processing charge was funded by the Baden-Wuerttemberg Ministry of Science, Research and Art and the University of Freiburg in the funding programme Open Access Publishing. 7. References Banks, W. A., & Erickson, M. A. (2010). The blood-brain barrier and immune function and dysfunction. Neurobiol Dis, 37 (1), 26-32. doi:10.1016/j.nbd.2009.07.031 Bechmann, I., Galea, I., & Perry, V. H. (2007). What is the blood-brain barrier (not)? Trends Immunol, 28 (1), 5-11. doi:10.1016/j.it.2006.11.007 Bechter, K. (2013). Updating the mild encephalitis hypothesis of schizophrenia. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 42 , 71-91. doi:10.1016/j.pnpbp.2012.06.019 Blank T, Detje CN, Spieß A, Hagemeyer N, Brendecke SM, Wolfart J, Staszewski O, Zöller T, Papageorgiou I, Schneider J, Paricio-Montesinos R, Eisel UL, Manahan-Vaughan D, Jansen S, Lienenklaus S, Lu B, Imai Y, Müller M, Goelz SE, Baker DP, Schwaninger M, Kann O, Heikenwalder M, Kalinke U, Prinz M. Brain Endothelial- and Epithelial-Specific Interferon Receptor Chain 1 Drives Virus-Induced Sickness Behavior and Cognitive Impairment. Immunity. 2016 Apr 19;44(4):901-12. doi: 10.1016/j.immuni.2016.04.005. Cai, H. Q., Catts, V. S., Webster, M. J., Galletly, C., Liu, D., O'Donnell, M., Weickert, T. W., & Weickert, C. S. (2020). Increased macrophages and changed brain endothelial cell gene expression in the frontal cortex of people with schizophrenia displaying inflammation. Mol Psychiatry, 25 (4), 761-775. doi:10.1038/s41380-018-0235-x Carvey, P. M., Hendey, B., & Monahan, A. J. (2009). The blood-brain barrier in neurodegenerative disease: a rhetorical perspective. Journal of Neurochemistry, 111 (2), 291-314. doi:10.1111/j.1471-4159.2009.06319.x Deisenhammer, F., Bartos, A., Egg, R., Gilhus, N. E., Giovannoni, G., Rauer, S., & Sellebjerg, F. (2006). Guidelines on routine cerebrospinal fluid analysis. Report from an EFNS task force. Eur J Neurol, 13 (9), 913-922. doi:10.1111/j.1468-1331.2006.01493.x Endres, D., Meixensberger, S., Dersch, R., Feige, B., Stich, O., Venhoff, N., Matysik, M., Michel, M., Runge, K., Nickel, K., Urbach, H., Domschke, K., Prüss, H., & Tebartz van Elst, L. (2020). Cerebrospinal fluid, antineuronal autoantibody, EEG, and MRI findings from 992 patients with schizophreniform and affective psychosis. Transl Psychiatry. 10(1):279. doi: 10.1038/s41398-020-00967-3. Endres, D., Perlov, E., Baumgartner, A., Hottenrott, T., Dersch, R., Stich, O., & Tebartz van Elst, L. (2015). Immunological findings in psychotic syndromes: a tertiary care hospital's CSF sample of 180 patients. Front Hum Neurosci, 9 , 476. doi:10.3389/fnhum.2015.00476 Kong, D. H., Kim, Y. K., Kim, M. R., Jang, J. H., & Lee, S. (2018). Emerging Roles of Vascular Cell Adhesion Molecule-1 (VCAM-1) in Immunological Disorders and Cancer. Int J Mol Sci, 19 (4). doi:10.3390/ijms19041057 Krönig, H., Riedel, M., Schwarz, M. J., Strassnig, M., Möller, H. J., Ackenheil, M., & Müller, N. (2005). ICAM G241A Polymorphism and Soluble ICAM-1 Serum Levels: Evidence for an Active Immune Process in Schizophrenia. Neuroimmunomodulation, 12 (1), 54-59. doi:10.1159/000082364 Kuzior, H., Fiebich, B.L., Yousif, N.M., Saliba, S.W., Ziegler, C., Nickel, K., Maier, S.J., Süß, P., Runge, K., Matysik, M., Dersch, R., Berger, B., Robinson, T., Venhoff, N., Kessler, F., Blank, T., Domschke, K., Tebartz van Elst, L., Endres, D (2020). Increased IL-8 Concentrations in the Cerebrospinal Fluid of Patients with Unipolar Depression. Comprehensive Psychiatry. In press. Lawson, C., & Wolf, S. (2009). ICAM-1 signaling in endothelial cells. Pharmacol Rep, 61 (1), 22-32. doi:10.1016/s1734-1140(09)70004-0 Mantere O, Trontti K, García-González J, Balcells I, Saarnio S, Mäntylä T, Lindgren M, Kieseppä T, Raij T, Honkanen JK, Vaarala O, Hovatta I, Suvisaari J. Immunomodulatory effects of antipsychotic treatment on gene expression in first-episode psychosis. J Psychiatr Res. 2019 Feb;109:18-26. doi: 10.1016/j.jpsychires.2018.11.008. Epub 2018 Nov 10. Muller, N. (2019). The Role of Intercellular Adhesion Molecule-1 in the Pathogenesis of Psychiatric Disorders. Front Pharmacol, 10 , 1251. doi:10.3389/fphar.2019.01251 Müller, N., & Bechter, K. (2013). The mild encephalitis concept for psychiatric disorders revisited in the light of current psychoneuroimmunological findings. Neurology Psychiatry and Brain Research, 19 . doi:10.1016/j.npbr.2013.04.004 Najjar, S., Pahlajani, S., De Sanctis, V., Stern, J. N. H., Najjar, A., & Chong, D. (2017). Neurovascular Unit Dysfunction and Blood-Brain Barrier Hyperpermeability Contribute to Schizophrenia Neurobiology: A Theoretical Integration of Clinical and Experimental Evidence. Front Psychiatry, 8 , 83. doi:10.3389/fpsyt.2017.00083 Najjar, S., Pearlman, D. M., Devinsky, O., Najjar, A., & Zagzag, D. (2013). Neurovascular unit dysfunction with blood-brain barrier hyperpermeability contributes to major depressive disorder: a review of clinical and experimental evidence. J Neuroinflammation, 10 , 142. doi:10.1186/1742-2094-10-142 Nguyen, T. T., Dev, S. I., Chen, G., Liou, S. C., Martin, A. S., Irwin, M. R., Carroll, J. E., Tu, X., Jeste, D. V., & Eyler, L. T. (2018). Abnormal levels of vascular endothelial biomarkers in schizophrenia. Eur Arch Psychiatry Clin Neurosci, 268 (8), 849-860. doi:10.1007/s00406-017-0842-6 Orlovska-Waast, S., Köhler-Forsberg, O., Brix, S. W., Nordentoft, M., Kondziella, D., Krogh, J., & Benros, M. E. (2019). Cerebrospinal fluid markers of inflammation and infections in schizophrenia and affective disorders: a systematic review and meta-analysis. Molecular Psychiatry, 24 (6), 869-887. doi:10.1038/s41380-018-0220-4 Pollak, T. A., Drndarski, S., Stone, J. M., David, A. S., McGuire, P., & Joan Abbott, N. (2018). The blood–brain barrier in psychosis. Lancet Psychiatry; 5: 79–92 . Pollak, T.A., Lennox, B.R., Müller, S., Benros ,M.E., Prüss, H., Tebartz van Elst, L., Klein, H., Steiner, J., Frodl, T., Bogerts, B., Tian, L., Groc, L., Hasan, A., Baune, B.T., Endres, D., Haroon, E., Yolken, R., Benedetti, F., Halaris, A., Meyer, J.H., Stassen, H., Leboyer, M., Fuchs, D., Otto, M., Brown, D.A., Vincent, A., Najjar, S., Bechter, K.. Autoimmune psychosis: an international consensus on an approach to the diagnosis and management of psychosis of suspected autoimmune origin. Lancet Psychiatry. 2020 Jan;7(1):93-108. doi: 10.1016/S2215-0366(19)30290-1. Epub 2019 Oct 24. Radu, G., Luca, C., Petrescu, L., Bordejevic, D. A., Tomescu, M. C., Andor, M., Citu, I., Mavrea, A., Buda, V., Tomescu, C., Borcan, F., & Dehelean, L. (2020). The Predictive Value of Endothelial Inflammatory Markers in the Onset of Schizophrenia. Neuropsychiatr Dis Treat, 16 , 545-555. doi:10.2147/ndt.S240349 Ramos, T. N., Bullard, D. C., & Barnum, S. R. (2014). ICAM-1: isoforms and phenotypes. J Immunol, 192 (10), 4469-4474. doi:10.4049/jimmunol.1400135 Reiber, H., & Peter, J. B. (2001). Cerebrospinal fluid analysis: disease-related data patterns and evaluation programs. 184 (2), 101-122. doi:10.1016/s0022-510x(00)00501-3 Reiber, H., & Uhr, M. (2018). Physiologie des Liquors. In P. Berlit (Ed.), Klinische Neurologie (pp. 1-19). Berlin, Heidelberg: Springer Berlin Heidelberg. Schwarz, M. J., Ackenheil, M., Riedel, M., & Müller, N. (1998). Blood-cerebrospinal fluid barrier impairment as indicator for an immune process in schizophrenia. Neuroscience Letters, 253 (3), 201-203. doi:10.1016/s0304-3940(98)00655-7 Schwarz, M. J., Riedel, M., Ackenheil, M., & Müller, N. (2000). Decreased levels of soluble intercellular adhesion molecule-1 (sICAM-1) in unmedicated and medicated schizophrenic patients. Biological Psychiatry, 47 (1), 29-33. doi:10.1016/s0006-3223(99)00206-1 Serlin, Y., Shelef, I., Knyazer, B., & Friedman, A. (2015). Anatomy and physiology of the blood–brain barrier. Seminars in Cell & Developmental Biology, 38 , 2-6. doi:10.1016/j.semcdb.2015.01.002 Stefanovic, M. P., Petronijevic, N., Dunjic-Kostic, B., Velimirovic, M., Nikolic, T., Jurisic, V., Lackovic, M., Damjanovic, A., Totic-Poznanovic, S., Jovanovic, A. A., & Ivkovic, M. (2016). Role of sICAM-1 and sVCAM-1 as biomarkers in early and late stages of schizophrenia. J Psychiatr Res, 73 , 45-52. doi:10.1016/j.jpsychires.2015.11.002 Stich, O., Andres, T.A., Gross, C.M., Gerber, S.I., Rauer, S., Langosch, J.M. (2015). An observational study of inflammation in the central nervous system in patients with bipolar disorder. Bipolar Disord. 17(3):291-302. doi: 10.1111/bdi.12244. Epub 2014 Aug 11. Tumani, H., Huss, A., & Bachhuber, F. (2017). The cerebrospinal fluid and barriers - anatomic and physiologic considerations. Handb Clin Neurol, 146 , 21-32. doi:10.1016/b978-0-12-804279-3.00002-2 Varatharaj A, Galea I. The blood-brain barrier in systemic inflammation. Brain Behav Immun. 2017 Feb;60:1-12. doi: 10.1016/j.bbi.2016.03.010. Epub 2016 Mar 16. Wildemann, B., Oschmann, P., & Reiber, H. (2010). Laboratory diagnosis in neurology (1st edition ed.). Stuttgart: Thieme. Yousef H, Czupalla CJ, Lee D, Chen MB, Burke AN, Zera KA, Zandstra J, Berber E, Lehallier B, Mathur V, Nair RV, Bonanno LN, Yang AC, Peterson T, Hadeiba H, Merkel T, Körbelin J, Schwaninger M, Buckwalter MS, Quake SR, Butcher EC, Wyss-Coray T. Aged blood impairs hippocampal neural precursor activity and activates microglia via brain endothelial cell VCAM1. Nat Med. 2019 Jun;25(6):988-1000. doi: 10.1038/s41591-019-0440-4. Epub 2019 May 13. Tables Table 1: Overview of findings measuring levels of sICAM-1 and sVCAM-1 in patients with schizophrenia-spectrum disorders (reviewed by Müller, 2019). Abbreviations: CSF, cerebrospinal fluid; ELISA, enzyme-linked immunosorbent assay; sICAM-1, soluble intercellular adhesion molecule 1; BCSFB, blood-CSF-barrier; PCR, polymerase chain reaction; mRNA, messenger RNA; VEGF, vascular endothelial growth factor; sVCAM-1, vascular cell adhesion molecule 1; ↑, higher; =, normal; ↓, lower; Ø, none. Sample material Method Research group Schizophrenia-spectrum disorder group Control group Results CSF ELISA Schwarz et al., 1998 n=40 Ø Significant association of sICAM-1 and BCSFB CSF ELISA Schwarz et al., 2000 n=18 Ø Significant positive correlation of sICAM-1 with negative symptomatology and disease duration Cortex tissue PCR Cai et al., 2018 n=37 n=37 ↑ expression of ICAM-1 mRNA Plasma Multiplexing immuneassay (Luminex®) Cai et al., 2018 n=78 n=73 ↑ levels of sICAM-1 Plasma Multiplexing immuneassay (Meso Scale Discovery MULTI-SPOT®) Nguyen et al., 2018 n=134 n=113 ↑ levels of ‘vascular endothelial index’ including VEGF, sICAM-1, sVCAM-1 Serum ELISA Schwarz et al., 2000 n=72 n=38 ↓ levels of sICAM-1 and increase of sICAM-1 during treatment Serum ELISA Kroenig et al., 2005 n=70 n=128 ↓ levels of sICAM-1 and relationship to ICAM-1 G214A polymorphism Serum ELISA Stefanovic et al., 2016 n=80 n=80 = levels of sICAM-1 in early-stage, ↑ levels of sICAM-1 in late-stage and associations with severity and disease duration Table 2: Clinical data of patients with schizophrenia-spectrum disorder and depressive disorder. Abbreviations: CSF = cerebrospinal fluid, MRI = magnetic resonance imaging, EEG = electroencephalography, F = female, M = male, SD = standard deviation, SSRI = selective serotonin reuptake inhibitor, SSNRI = selective serotonin/noradrenaline reuptake inhibitor. Schizophrenia-spectrum disorder (N=40) Depressive disorder (N=39) Sex 16 M : 24 F 14 M : 25 F Age (Mean±SD, range) 33.63 ± 13.38 (18-65years) 32.54 ± 7.65 (18-44 years) Clinical syndrome and characteristics Severe depressive episode With psychotic symptoms Without psychotic symptoms Schizophrenia spectrum disorder Paranoid-hallucinatory Hebephrenic Catatonic Delusional disorders Schizoaffective - Depressive - Manic - Mixed Acute polymorphic psychotic 40 (100%) 25 (63%) 1 (3%) 1 (3%) 1 (3%) 11 (28%) 6 (15%) 3 (8%) 2 (5%) 1 (3%) 39 (100%) 7 (18%) 32 (82%) Course of disease Recurrent/chronic First episode 27 (68%) 13 (33%) 27 (69%) 12 (31%) Neurologic comorbidity Seizures/Attacks Traumatic Polyneuropathy Migraine/Headache Overall 2 (5%) 3 (8%) 0 (0%) 1 (3%) 6 (15%) 0 (0%) 0 (0%) 0 (0%) 1 (3%) 1 (3%) Psychotropic medication at the time of sampling SSRI SSNRI Tricyclic antidepressants Bupropion Mirtazapine Typical neuroleptics Atypical neuroleptics Lithium Anticonvulsant Benzodiazepine Unmedicated 4 (10%) 1 (3%) 0 (0%) 4 (10%) 1 (3%) 9 (23%) 40 (100%) 7 (18%) 7 (18%) 9 (23%) 0 (0%) 9 (23%) 21 (54%) 8 (21%) 4 (10%) 6 (15%) 4 (10%) 21 (54%) 9 (23%) 1 (3%) 3 (8%) 2 (5%) Table 3: Demographic data. Schizophrenia-spectrum disorder (N=40) Depressive disorder (N=39) Marital status Single Married Divorced Widowed Unknown 30 (77%) 6 (15%) 1 (3%) 1 (3%) 2 (5%) 31 (79%) 6 (15%) 2 (5%) 0 (0%) 0 (0%) Level of education Low Middle High Unknown 11 (28%) 7 (18%) 19 (48%) 3 (8%) 2 (5%) 8 (21%) 28 (72%) 1 (3%) Work situation Unemployed Working In training Retired Housewife/-man Unknown 7 (18%) 13 (33%) 11 (28%) 6 (15%) 2 (5%) 1 (3%) 6 (15%) 20 (51%) 11 (28%) 1 (3%) 1 (3%) 0 (0%) Housing situation Alone With partner/family With parents/guardian Other Unknown 13 (33%) 11 (28%) 12 (30%) 4 (10%) 0 (0%) 18 (47%) 10 (26%) 10 (26%) 0 (0%) 1 (3%) Suicide attempts None One Two Three Four Five Six Unclear 28 (70%) 2 (5%) 4 (10%) 1 (3%) 1 (3%) 1 (3%) 0 (0%) 3 (8%) 34 (87%) 2 (5%) 2 (5%) 0 (0%) 0 (0%) 0 (0%) 1 (3%) 0 (0%) Number of earlier inpatient treatments None One Two Three Four Five > Five Unclear 12 (30%) 6 (15%) 3 (8%) 3 (8%) 2 (5%) 5 (13%) 7 (18%) 2 (5%) 15 (38%) 12 (31%) 6 (15%) 2 (5%) 1 (3%) 2 (5%) 1 (3%) 0 (0%) Table 4: Cell adhesion molecule levels in the cerebrospinal fluid. Abbreviations: PAI-1 = plasminogen activator inhibitor 1, SD = standard deviation, s-ICAM-1 = soluble intercellular adhesion molecule-1, sVCAM-1 = soluble vascular cell adhesion molecule-1. Schizophrenia-spectrum disorder (N=40) Depressive disorder (N=39) Statistics PAI-1 (pg/ml) (Mean ± SD) 72.006 ± 46.810 30.756 ± 23.397 (N=38) F= 13.312 p<0.001 sICAM-1 (pg/ml) (Mean ± SD) 1196.252 ± 768.714 466.205 ± 277.053 F=12.716 p<0.001 sVCAM-1 (pg/ml) (Mean ± SD) 456.197 ± 155.549 234.195 ± 151.553 F=0.239 p<0.001 Table 5: Findings in cerebrospinal fluid routine diagnostics. Abbreviations: WBC = white blood cell, SD = standard deviation, y. = years, IgG = immunoglobulin G, CSF = cerebrospinal fluid, OCBs = oligoclonal bands. * Two findings were borderline positive: A first patient had some weak identical bands in CSF and serum, a second patient had an isolated OCB in the CSF. Reference Schizophrenia-spectrum disorder (N=40) Depressive disorder (N=39) Statistics WBC counts (Mean ± SD) in /µl 1.85 ± 1.46 1.82 ± 1.23 F=0.066 p=0.923 Number of increased WBC counts < 5 /µl ↑: 3 (8%) ↑: 2 (5%) Chi 2 =0.187 p=0.665 Protein concentration (Mean ± SD) in mg/l 406.45 ± 196.15 418.87 ± 153.68 F=0.599 p=0.755 Number of increased protein concentration < 450 mg/l ↑: 12 (30%) ↑: 14 (36%) Chi 2 =0.311 p=0.577 Albumin quotient (Mean ± SD) 5.02 ± 2.29 5.12 ± 2.05 F=0.158 p=0.834 Number of increased albumin quotients <40y.: < 6.5 x 10 -3 40-60y.: 60y.: < 9.3 x 10 -3 ↑: 6 (15%) ↑: 8 (21%) Chi 2 =0.412 p=0.521 IgG-Index (Mean ± SD) in mg/l 0.49 ± 0.04 0.49 ± 0.09 F=1.813 p=0.731 Number of increased IgG indices < 0.7 mg/l ↑: 0 (0%) ↑: 1 (3%) Chi 2 =1.039 p=0.308 OCBs in CSF negative 1* (3%) 2 (5%) Chi 2 =0.556 p=0.346 Cite Share Download PDF Status: Published Journal Publication published 22 Jun, 2021 Read the published version in Diagnostics → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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16:37:52","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-121960/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-121960/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.3390/diagnostics11071134","type":"published","date":"2021-06-22T13:20:28+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":4545125,"identity":"614b5203-d711-47ea-9752-3c3f1efc3b37","added_by":"auto","created_at":"2020-12-28 16:34:32","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":55524,"visible":true,"origin":"","legend":"The albumin quotient significantly correlated with the vascular cell adhesion molecule-1 in patients with schizophrenia spectrum disorders (sVCAM-1; r=0.583, p\u003c0.001).","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-121960/v1/c69249f94246eaf0bba11d84.jpg"},{"id":60250535,"identity":"9f7a64d6-fb2f-441f-9cb4-af67b123501c","added_by":"auto","created_at":"2024-07-14 13:20:36","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1040254,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-121960/v1/b6086780-fd1d-47ea-98d6-048567b235a8.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003eUpregulation of sICAM-1 and sVCAM-1 Levels in the Cerebrospinal Fluid of Patients with Schizophrenia Spectrum Disorders\u003c/p\u003e","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eImmunological explanatory approaches are becoming increasingly important in schizophrenia research (Pollak et al., 2020). Schizophrenia spectrum disorders were interpreted by several authors as complex neuropsychiatric disorders involving an activated inflammatory response leading to mild neuroinflammation (Bechter, 2013; Muller, 2019; M\u0026uuml;ller et al., 2013; Nguyen et al., 2018; Stefanovic et al., 2016). In this context, the functions of the blood\u0026ndash;brain barrier (BBB) and the blood\u0026ndash;cerebrospinal fluid (CSF) barrier (BCSFB) play a central role (Pollak et al., 2018), and a number of clinical studies showed alterations in biomarkers associated with the BBB/BCSFB (Endres et al., 2020; Endres et al., 2015; Najjar et al., 2017; Najjar et al., 2013; Orlovska-Waast et al., 2019). The central nervous system (CNS) is surrounded by the dynamic and metabolically active CSF and is separated from the peripheral circulation by several barriers, the most prominent are the BBB and the BCSFB (Banks et al., 2010; Deisenhammer et al., 2006; Tumani et al., 2017; Wildemann et al., 2010). The BBB/BCSFB form the primary interface that exerts key functions in brain homeostasis and immune protection (Banks et al., 2010; Najjar et al., 2017). One of the most notable components responsible for barrier integrity are the brain capillary endothelial cells that sustain a paracellular pathway with a highly selective permeability mediated by selective transport vesicles and tight junctions (Carvey et al., 2009; Pollak et al., 2018; Serlin et al., 2015). In this cerebral microvascular endothelium, different intercellular adhesion molecules, particularly intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), are expressed under chronic inflammatory conditions (Kong et al., 2018; M\u0026uuml;ller, 2019). Endothelial cells are not only a passive barrier but also immunologically active themselves. For example, they can produce chemokines (Blank et al., 2016), and endothelial VCAM-1 is associated with age- and inflammation-induced microglia activation, impaired neurogenesis and cognitive deficits. These changes are diminished by antagonization of VCAM-1 and can occur even without disturbance of the BBB/BCSFB parameters or infiltration of immune cells (Yousef et al., 2019).\u003c/p\u003e\n\u003cp\u003ePrevious studies comparing patients with schizophrenia spectrum disorder and controls revealed contradictory findings on soluble ICAM-1 (sICAM-1) and soluble VCAM-1 (sVCAM-1) levels when obtained with different methods and samples, including serum, CSF, and postmortem CNS tissues, as summarized in Table 1 (M\u0026uuml;ller, 2019).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eThe objective of this study\u003c/strong\u003e was to conduct the first controlled CSF study that investigates cell adhesion molecules in patients with schizophrenia spectrum disorders and in a psychiatric control group. More specifically, we (1) compared the levels of different cell adhesion molecules in the CSF of patients with schizophrenia spectrum disorders to those of patients with unipolar depression and (2) we analyzed the association of these cell adhesion molecules with the established CSF markers of BBB/BCSFB function (i.e., total CSF protein and albumin quotient [AQ]).\u003c/p\u003e"},{"header":"2. Participants And Methods","content":"\u003cp\u003eThis study was part of a larger retrospective project that was approved by the local ethics committee (Faculty of Medicine, University of Freiburg, ethical vote no. 396/18). Lumbar punctures were performed after careful gathering of information and after obtaining written informed consent as part of clinical routine to rule out organic causes of psychiatric symptoms This study was carried out in accordance with relevant guidelines and regulations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.1 Study sample\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 40 patients diagnosed with schizophrenia spectrum disorder and 39 patients diagnosed with unipolar depression were included in this study (for clinical and demographic details see tables 2 and 3). Based on the predominant clinical syndrome, patients were classified according to the criteria set by the International Statistical Classification of Diseases and Related Health Problems, 10th revision (ICD-10). In the schizophrenia cohort, 13 patients went through their first episode and 27 suffered from a chronic or recurrent manifestation, with chronic being defined as a period of more than two years. In the depression cohort, 12 patients suffered from their first episode and 27 patients were in a chronic or recurrent stage. All 39 patients in the depression cohort were diagnosed with a severe depressive episode.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.2 Cerebrospinal fluid analysis and instrumental diagnostics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe routine CSF analysis included the determination of white blood cell (WBC) count, protein concentration, AQ, immunoglobulin (Ig)G index, and oligoclonal bands (OCBs) according to an established methodology (c.f. Endres et al., 2015, 2020). The measurements were carried out in the CSF laboratory of the University Hospital Freiburg (https://www.uniklinik-freiburg.de/neurologie/klinik/diagnostische-einrichtungen/liquor-labor.html). Electroencephalography (EEG) and cerebral magnetic resonance imaging (MRI) were offered to all patients as part of the clinical routine work-up.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3. Measurement of cell-adhesions markers\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe adhesion molecules were quantified through a magnetic bead-based multiplex immunoassay by using a Human Adhesion Magnetic 6-Plex Panel (ThermoFisher, Waltham, MA); a MAGPIX\u0026reg; machine (ThermoFisher, Waltham, MA) was used to read and analyze the assay. The panel utilized to investigate sICAM-1, sVCAM-1, plasminogen activator inhibitor 1 (PAI-1), P-selectin, E-selectin, and platelet endothelial cell adhesion molecule-1 (PECAM) was used in accordance with the manufacturer\u0026rsquo;s specifications, with the exception of using undiluted CSF samples, as this panel was originally not established for CSF analysis. The reported values are corrected for the different dilution. To determine whether the calculated concentrations of the individual adhesion molecules were reliable, we investigated the mean fluorescent intensity after deduction of the blank value, which is known as the net median fluorescence intensity (NetMFI), as well as the number of magnetic beads measured per analyte per well (bead count; cf. Kuzior et al., 2020). In this study, all values with a NetMFI below the lowest standard of the standard curve of the respective cell adhesion molecule and all wells with a bead count below 20 were excluded (c.f. with Kuzior et al., 2020). Only the samples that were measurable (and therefore not below the detection level) for \u0026gt;50% of the analytes were analyzed. The adhesion molecule concentrations below the detection level were set to zero.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.4 Data handling and statistical analyses\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData was analyzed using the Statistical Package for the Social Sciences (SPSS), version 24 (IBM Corp., Armonk, NY). Group comparisons for categorical variables were conducted using the Pearson\u0026rsquo;s chi-squared test, whereas group comparisons for continuous variables were performed using two-sided independent sample t-tests. A Pearson correlation between CSF basic parameters (WBC count, protein concentration, AQ, and IgG index) and cell adhesion molecules (sICAM-1, sVCAM-1, and PAI-1) was separately performed for each group (schizophrenia and unipolar depression). A p-value of \u0026lt;0.05 was set to indicate statistical significance. No correction for multiple testing was performed given that an exploratory approach was implemented in this study.\u003c/p\u003e"},{"header":"3. Results","content":"\u003cp\u003e\u003cstrong\u003e3.1 Sociodemographic data\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe sociodemographic data is summarized in Tables 2 and 3. The schizophrenia spectrum and depressive patient groups were matched for age (F=11.455, p=0.660) and sex (Chi\u003csup\u003e2\u003c/sup\u003e=0.141, p=0.707).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.2 Cell adhesion molecules in the cerebrospinal fluid\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe cell adhesion molecules sICAM-1, sVCAM-1, and PAI-1 in the CSF were successfully measured. The other parameters could not be measured sufficiently. The levels of sICAM-1 (p\u0026lt;0.001), sVCAM-1 (p\u0026lt;0.001), and PAI-1 (p\u0026lt;0.001) in the CSF were significantly higher in the patients with schizophrenia spectrum disorder than in those with unipolar depression (Table 4). Subgroup analyses between patients with schizoaffective (N=11) and the other patients from the schizophrenia spectrum disorder group (N=29) had similar mean ages (F=0.213, p=0.345). Both groups did not differ in the concentrations of sICAM (F=0.042, p=0.541), sVCAM (F=3.029, p=0.054), and PAI (F=0.057, p=0.239). The sICAM-1, sVCAM-1, and PAI-1 levels in patients with first-episode schizophrenia spectrum disorder or depression did not significantly differ from those in patients with a chronic/recurrent state of the diseases (data not shown in detail).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3. Basic cerebrospinal fluid findings and instrumental diagnostics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe routine findings for CSF diagnostics are presented in Table 5. Overall, no significant differences in WBC counts, protein concentration, AQs, IgG indices, and rate of OCBs were observed between the schizophrenia and depression groups. Also, the number of total abnormalities in MRI (in 63% of patients with schizophrenia-spectrum disorders and in 67% of patients with depression; Chi\u003csup\u003e2\u003c/sup\u003e=0.278, p=0.598) in the two groups did not differ significantly, although EEG pathologies occurred more frequently in the schizophrenia group (in 25%; versus in 5% of the patients with depression; Chi\u003csup\u003e2\u003c/sup\u003e=6.053, p=0.014).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.4 Correlation analyses\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn the schizophrenia spectrum disorder cohort, the CSF total protein concentration correlated significantly with the sVCAM-1 levels (r=0.505, p=0.001), and the AQ correlated with the sVCAM-1 (r=0.583, p\u0026lt;0.001; see Figure 1) and PAI-1 levels (r=0.337, p=0.033). By contrast, the levels of the cell adhesion molecules were not significantly correlated with clinical features, including suicide attempts and the number of earlier inpatient stays. In the unipolar depression cohort, no significant correlations of sICAM-1, sVCAM-1, and PAI-1 levels with WBC count, CSF total protein, AQ, and IgG index were detected. Also, the levels of the adhesion molecules were not significantly correlated with clinical features, including suicide attempts and the number of earlier inpatient stays.\u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThe results of this study revealed significantly elevated sICAM-1 and sVCAM-1 levels in patients suffering from schizophrenia spectrum disorders compared to patients with depressive disorders. Oriented to established CSF reference values (using ELISA-technique) of sICAM according to which CSF values \u0026lt; 300 pg/mL must be assumed in healthy controls, the values in depressed patients (Mean: 466.205 pg/ml) have been found to be already slightly increased and those in schizophreniform disorders were clearly elevated and on average four times above the established reference value (Mean: 1196 pg/ml) (for reference values see: https://07525720-0688-4380-840d-0a4af942fef7.filesusr.com/ugd/92c932_454e4d6908d94f64b3623b621179eade.pdf). An upregulation of these signaling molecules in the schizophrenia spectrum disorder cohort may firstly be indicative of neuroinflammatory processes followed by a proinflammatory immune response (M\u0026uuml;ller, 2019; Ramos et al., 2014). Second, the overexpression of the adhesion molecules may be related to an impairment of the BBB/BCSFB (M\u0026uuml;ller, 2019; Schwarz et al., 1998). Accordingly, the sVCAM-1 levels correlated with the AQ (which is considered the gold standard estimating the integrity of the BBB/BCSFB) in patients with schizophrenia spectrum disorders (Pollak et al., 2018; Reiber et al., 2001; Reiber et al., 2018; Tumani et al., 2017; Wildemann et al., 2010).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e4.1 Integration of our findings into the context of the current research\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIncreased sICAM-1 levels have been observed in multiple inflammatory and cell-mediated autoimmune disorders (Radu et al., 2020). The current findings of increased CSF levels of this molecule are consistent with the reported significant elevation of plasma sICAM-1 levels in patients with schizophrenia spectrum disorder (Cai et al., 2020; Stefanovic et al., 2016). Stefanovic et al. (2016) discerned increased sICAM-1 levels in patients at a late stage of the disease, whereas no difference between healthy controls and patients with schizophrenia spectrum disorder was found in the early disease stages. By contrast, decreased peripheral levels of sICAM-1 and sVCAM-1 have been reported in another cohort of patients with schizophrenia spectrum disorders (Schwarz et al., 2000). In the explanatory approach, these contradictory findings may be explained in the light of a dysfunctional neuroendocrine immune communication and a reduced immune response during the acute onset of schizophrenia, whereas an overexpression could be an indication of an immune activation during a prolonged course of the disease (M\u0026uuml;ller, 2019; Nguyen et al., 2018). Consistent with this view, 68% (27 out of 40) of the patients with schizophrenia in the present cohort suffered from a recurrent/chronic course of the disease. However, we were not able to detect significant differences that distinguish patients with the first episode from those with the recurrent/chronic stage. In the first, uncontrolled CSF study on cell adhesion molecules in schizophrenia, a significant correlation was found between sICAM-1 level and AQs (Schwarz et al., 1998); this finding could not be replicated in our data. However, a significant positive correlation between sVCAM-1 levels and AQs was discerned (see Figure 1).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e4.2 Pathophysiological and clinical considerations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAn increase in circulating proinflammatory cytokines was determined in the context of multiple psychiatric disorders (Cai et al., 2020; Lawson et al., 2009; Nguyen et al., 2018). Different inflammatory mediators (e.g., TNF\u0026alpha;, IL-1\u0026beta;, and IFN\u0026gamma;) induce the expression levels of ICAM-1 and VCAM-1 (Kong et al., 2018; Najjar et al., 2017; Najjar et al., 2013; Nguyen et al., 2018). ICAM-1 (CD54) is a transmembrane glycoprotein of approximately 100 kDa in size; it belongs to the immunoglobulin supergene family and it consists of five tandem immunoglobulin-like domains (Kr\u0026ouml;nig et al., 2005; Lawson et al., 2009; Muller, 2019; Ramos et al., 2014). In the CNS, ICAM-1 is expressed most notably in microglial cells, astrocytes, and endothelial cells in the white and grey matter (M\u0026uuml;ller, 2019; Ramos et al., 2014). The ligations of ICAM-1 to the lymphocyte function-associated molecule 1 on the surface of endothelial cells and to the macrophage-associated antigen-1 receptors on leucocytes contribute to the immune cell infiltration during an inflammatory response (Cai et al., 2020; Kr\u0026ouml;nig et al., 2005; Lawson et al., 2009). ICAM-1 enables the trans-endothelial migration of leukocytes to the site of inflammation and plays an important role in immunological synapse formation (the interaction between antigen-presenting cells and T cells), in lymphocyte activation, and in numerous cellular immune responses (Cai et al., 2020; Lawson et al., 2009; Muller, 2019; Radu et al., 2020; Ramos et al., 2014). Arising from alternative splicing and/or proteolytic cleavage of membrane-bound ICAM-1 messenger RNA, a circulating soluble form of ICAM-1 (sICAM-1) consisting of the complete extracellular domain can be found in serum and CSF (Kr\u0026ouml;nig et al., 2005; Lawson et al., 2009; Ramos et al., 2014). The sICAM-1 and its membrane-bound form exert similar functions (M\u0026uuml;ller, 2019). The elevated levels of sICAM-1 in CSF\u0026mdash;as demonstrated in the current study\u0026mdash;or in serum may therefore be indicative of the upregulated state of the membrane-bound ICAM-1 in the brain (M\u0026uuml;ller, 2019). VCAM-1 (CD106) is a 90-kDa glycoprotein predominantly expressed in endothelial cells (Kong et al., 2018). VCAM-1 regulates the pathway involved in leukocyte recruitment and transendothelial migration during inflammation via the interaction of its domain 1 (and/or 4) with \u0026alpha;4\u0026beta;1 integrin (Kong et al., 2018). In most cell types, the expression of leucocyte adhesion molecules, such as ICAM-1 and VCAM-1, is low under non-inflammatory conditions, whereas a state of overexpression was described in many pathological states, especially during chronic inflammatory processes (Kong et al., 2018; Muller, 2019; Pollak et al., 2018; Ramos et al., 2014). Given that ICAM-1 is widely expressed in tissues, ICAM-1 levels may thus indicate the general level of inflammation (Radu et al., 2020); by contrast, VCAM-1 seems to indicate the conditions of the cerebral endothelium and the dendritic cells more precisely and thus could be used to assess endothelial dysfunction (Radu et al., 2020). Correlations were observed between the elevated levels of ICAM-1 and the progression and severity of cancer, cardiovascular disease, and autoimmune disorders (Lawson et al., 2009; Muller, 2019) as well as between VCAM-1 and the progression of various immunological disorders, including rheumatoid arthritis, and cancer (Kong et al., 2018). In patients with schizophrenia spectrum disorders, the current study showed evidence of upregulated ICAM-1 and VCAM-1 levels, which may partially reflect the occurrence of leukocyte transendothelial recruitment and adhesion (M\u0026uuml;ller, 2019). The overexpression of ICAM-1 and VCAM-1 near the endothelial layer of the vessel wall impairs the vascular endothelial mitochondrial oxidative metabolism and directly destabilizes endothelial tight junctions (Kong et al., 2018; Najjar et al., 2017; Najjar et al., 2013; Nguyen et al., 2018). These processes increase the BBB/BCSFB permeability and allow the inappropriate migration of pro-inflammatory molecules into the brain parenchyma, enabling interactions between the innate and the peripheral adaptive immune systems in the brain (Bechmann et al., 2007; Carvey et al., 2009; Kong et al., 2018; Najjar et al., 2017). These theoretical considerations are supported by the correlation found between the sVCAM-1 levels and AQs in this study. In addition, it was earlier demonstrated that ICAM-1 and VCAM-1 can be elevated without an \u0026ldquo;open BBB/BCSFB\u0026rdquo;. In a review by Varatharaj and Galea (2017), disruptive and non-disruptive changes in the BBB were compared. The fact that there was no severe barrier disruption across the entire present cohort, but already high sICAM-1 and sVCAM-1 levels, could indicate that non-disruptive changes are underlying the pathological processes here. Therefore, the tight junctions would not be affected, but the endothelia would still let pass immune cells and/or secrete cytokines/chemokines. Thus, from a clinical perspective, sICAM-1 and sVCAM-1 could provide further information about the BBB/BCSFB function in addition to established CSF parameters such as AQ.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e4.3 Limitations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA limitation of the present study is its lack of a healthy control group. Especially with regard to CSF measurements. It is difficult to ethically justify lumbar punctures in a large group of healthy volunteers. Previously, we used a control group of patients with pseudotumor cerebri (e.g., Stich et al., 2015; Kuzior et al., 2020). In the current study, this approach was considered initially; unfortunately, we were unable to recruit a matched control group with an adequate sample size. However, we were able to use a clinical control group of patients with depressive disorders and established reference values. Patients with schizophrenia were routinely offered a lumbar puncture. In patients with depression, lumbar punctures were performed only in selected cases. These patients were not screened routinely and there probably is a selection bias towards severely depressed patients. In addition, the multiplexing immunoassay used was originally not established for CSF measurements, and its use may possibly have led to methodical inaccuracies and difficulties. However, most other methodological approaches have so far only been established for blood. Because CSF analysis was performed as part of clinical routine diagnostic work-up, the processes involved in sample processing were not completely standardized. The samples first underwent routine testing before being frozen at \u0026minus;80 \u0026deg;C. In future studies, samples should be processed directly according to established and pre-defined standard operating procedures. The influence of other possible contributing factors, including psychotropic medication or multiple vascular risk factors (Mantere et al., 2019; Muller, 2019; Nguyen et al., 2018), remains unclear and needs to be considered. In addition, we were not able to examine serum samples of the patients. This would have been helpful for the overall interpretation and comparison with the preliminary studies, which mostly only examined serum material. Finally, it is important to keep in mind that an overexpression of ICAM-1 is observed in a wide range of diseases and inflammation, even in depressive disorders; therefore, the present findings in patients with schizophrenia spectrum disorder probably do not reflect disease-specific processes (M\u0026uuml;ller, 2019). Due to the limitations mentioned above, the present results are to be considered preliminary and warrant replication in future studies.\u003c/p\u003e"},{"header":"5. Conclusions","content":"\u003cp\u003e\u003cspan lang=\"EN-US\"\u003eThe schizophrenia spectrum disorder pathophysiology may involve an altered immune response and a disturbed communication between the CNS and the immune system due to an impaired BBB/BCSFB. The present results indicate that the circulating immune signaling molecules sICAM-1 and sVCAM-1 might play a relevant role in this context. Further translational, prospective, and controlled studies in this novel psychoneuroimmunological field of research are needed.\u003c/span\u003e\u003c/p\u003e"},{"header":"6. Declarations","content":"\u003cp\u003e\u003cstrong\u003eDisclosure statement: \u003c/strong\u003eSMe: None. HK: None. BLF: None. PS: None. KR: None. BB: Received travel grants and/or training expenses from Bayer Vital GmbH, Ipsen Pharma GmbH, Norvartis, Biogen GmbH and Genzyme, as well as lecture fees from Ipsen Pharma GmbH, Alexion Pharma GmbH, Merck, Sanofi Genzyme and Roche. KN: None. DD: None. MAS: None. MM: None. SMa: None. KB: None. KD: Steering Committee Neurosciences, Janssen. LTvE: Advisory boards, lectures, or travel grants within the last three years: Roche, Eli Lilly, Janssen-Cilag, Novartis, Shire, UCB, GSK, Servier, Janssen and Cyberonics. DE: None.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions: \u003c/strong\u003eSMe, BLF, HK, LTvE and DE created the study design. BLF, KD, DE and LTvE supervised the study. HK and BLF were responsible for laboratory measurements. BB performed CSF basic analyses. SMe and SMa performed the statistical analyses. SMe wrote the paper and performed the data search. DE critically revised the manuscript. HK, KR, PS, KN, DD, MAS, MM, KB, KD, and LTvE supported the interpretation and revised the manuscript further. All authors were critically involved in the theoretical discussion and composition of the manuscript. All authors read and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgement:\u003c/strong\u003e DE was funded by the Berta-Ottenstein-Programme for Advanced Clinician Scientists, Faculty of Medicine, University of Freiburg. PS is a member of the research training group GRK2162 funded by the DFG (270949263/GRK2162) and is supported by the University Hospital Erlangen (ELAN project P059, IZKF clinician scientist program)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding: \u003c/strong\u003eThe article processing charge was funded by the Baden-Wuerttemberg Ministry of Science, Research and Art and the University of Freiburg in the funding programme Open Access Publishing.\u003c/p\u003e"},{"header":"7. References","content":"\u003cp\u003eBanks, W. A., \u0026amp; Erickson, M. A. (2010). The blood-brain barrier and immune function and dysfunction. \u003cem\u003eNeurobiol Dis, 37\u003c/em\u003e(1), 26-32. doi:10.1016/j.nbd.2009.07.031\u003c/p\u003e\n\u003cp\u003eBechmann, I., Galea, I., \u0026amp; Perry, V. H. (2007). What is the blood-brain barrier (not)? \u003cem\u003eTrends Immunol, 28\u003c/em\u003e(1), 5-11. doi:10.1016/j.it.2006.11.007\u003c/p\u003e\n\u003cp\u003eBechter, K. (2013). Updating the mild encephalitis hypothesis of schizophrenia. \u003cem\u003eProgress in Neuro-Psychopharmacology and Biological Psychiatry, 42\u003c/em\u003e, 71-91. doi:10.1016/j.pnpbp.2012.06.019\u003c/p\u003e\n\u003cp\u003eBlank T, Detje CN, Spie\u0026szlig; A, Hagemeyer N, Brendecke SM, Wolfart J, Staszewski O, Z\u0026ouml;ller T, Papageorgiou I, Schneider J, Paricio-Montesinos R, Eisel UL, Manahan-Vaughan D, Jansen S, Lienenklaus S, Lu B, Imai Y, M\u0026uuml;ller M, Goelz SE, Baker DP, Schwaninger M, Kann O, Heikenwalder M, Kalinke U, Prinz M. Brain Endothelial- and Epithelial-Specific Interferon Receptor Chain 1 Drives Virus-Induced Sickness Behavior and Cognitive Impairment. Immunity. 2016 Apr 19;44(4):901-12. doi: 10.1016/j.immuni.2016.04.005.\u003c/p\u003e\n\u003cp\u003eCai, H. Q., Catts, V. S., Webster, M. J., Galletly, C., Liu, D., O'Donnell, M., Weickert, T. W., \u0026amp; Weickert, C. S. (2020). Increased macrophages and changed brain endothelial cell gene expression in the frontal cortex of people with schizophrenia displaying inflammation. \u003cem\u003eMol Psychiatry, 25\u003c/em\u003e(4), 761-775. doi:10.1038/s41380-018-0235-x\u003c/p\u003e\n\u003cp\u003eCarvey, P. M., Hendey, B., \u0026amp; Monahan, A. J. (2009). The blood-brain barrier in neurodegenerative disease: a rhetorical perspective. \u003cem\u003eJournal of Neurochemistry, 111\u003c/em\u003e(2), 291-314. doi:10.1111/j.1471-4159.2009.06319.x\u003c/p\u003e\n\u003cp\u003eDeisenhammer, F., Bartos, A., Egg, R., Gilhus, N. E., Giovannoni, G., Rauer, S., \u0026amp; Sellebjerg, F. (2006). Guidelines on routine cerebrospinal fluid analysis. Report from an EFNS task force. \u003cem\u003eEur J Neurol, 13\u003c/em\u003e(9), 913-922. doi:10.1111/j.1468-1331.2006.01493.x\u003c/p\u003e\n\u003cp\u003eEndres, D., Meixensberger, S., Dersch, R., Feige, B., Stich, O., Venhoff, N., Matysik, M., Michel, M., Runge, K., Nickel, K., Urbach, H., Domschke, K., Pr\u0026uuml;ss, H., \u0026amp; Tebartz van Elst, L. (2020). Cerebrospinal fluid, antineuronal autoantibody, EEG, and MRI findings from 992 patients with schizophreniform and affective psychosis. Transl Psychiatry. 10(1):279. doi: 10.1038/s41398-020-00967-3.\u003c/p\u003e\n\u003cp\u003eEndres, D., Perlov, E., Baumgartner, A., Hottenrott, T., Dersch, R., Stich, O., \u0026amp; Tebartz van Elst, L. (2015). Immunological findings in psychotic syndromes: a tertiary care hospital's CSF sample of 180 patients. \u003cem\u003eFront Hum Neurosci, 9\u003c/em\u003e, 476. doi:10.3389/fnhum.2015.00476\u003c/p\u003e\n\u003cp\u003eKong, D. H., Kim, Y. K., Kim, M. R., Jang, J. H., \u0026amp; Lee, S. (2018). Emerging Roles of Vascular Cell Adhesion Molecule-1 (VCAM-1) in Immunological Disorders and Cancer. \u003cem\u003eInt J Mol Sci, 19\u003c/em\u003e(4). doi:10.3390/ijms19041057\u003c/p\u003e\n\u003cp\u003eKr\u0026ouml;nig, H., Riedel, M., Schwarz, M. J., Strassnig, M., M\u0026ouml;ller, H. J., Ackenheil, M., \u0026amp; M\u0026uuml;ller, N. (2005). ICAM G241A Polymorphism and Soluble ICAM-1 Serum Levels: Evidence for an Active Immune Process in Schizophrenia. \u003cem\u003eNeuroimmunomodulation, 12\u003c/em\u003e(1), 54-59. doi:10.1159/000082364\u003c/p\u003e\n\u003cp\u003eKuzior, H., Fiebich, B.L., Yousif, N.M., Saliba, S.W., Ziegler, C., Nickel, K., Maier, S.J., S\u0026uuml;\u0026szlig;, P., Runge, K., Matysik, M., Dersch, R., Berger, B., Robinson, T., Venhoff, N., Kessler, F., Blank, T., Domschke, K., Tebartz van Elst, L., Endres, D (2020). Increased IL-8 Concentrations in the Cerebrospinal Fluid of Patients with Unipolar Depression. Comprehensive Psychiatry. In press.\u003c/p\u003e\n\u003cp\u003eLawson, C., \u0026amp; Wolf, S. (2009). ICAM-1 signaling in endothelial cells. \u003cem\u003ePharmacol Rep, 61\u003c/em\u003e(1), 22-32. doi:10.1016/s1734-1140(09)70004-0\u003c/p\u003e\n\u003cp\u003eMantere O, Trontti K, Garc\u0026iacute;a-Gonz\u0026aacute;lez J, Balcells I, Saarnio S, M\u0026auml;ntyl\u0026auml; T, Lindgren M, Kiesepp\u0026auml; T, Raij T, Honkanen JK, Vaarala O, Hovatta I, Suvisaari J. Immunomodulatory effects of antipsychotic treatment on gene expression in first-episode psychosis. J Psychiatr Res. 2019 Feb;109:18-26. doi: 10.1016/j.jpsychires.2018.11.008. Epub 2018 Nov 10.\u003c/p\u003e\n\u003cp\u003eMuller, N. (2019). The Role of Intercellular Adhesion Molecule-1 in the Pathogenesis of Psychiatric Disorders. \u003cem\u003eFront Pharmacol, 10\u003c/em\u003e, 1251. doi:10.3389/fphar.2019.01251\u003c/p\u003e\n\u003cp\u003eM\u0026uuml;ller, N., \u0026amp; Bechter, K. (2013). The mild encephalitis concept for psychiatric disorders revisited in the light of current psychoneuroimmunological findings. \u003cem\u003eNeurology Psychiatry and Brain Research, 19\u003c/em\u003e. doi:10.1016/j.npbr.2013.04.004\u003c/p\u003e\n\u003cp\u003eNajjar, S., Pahlajani, S., De Sanctis, V., Stern, J. N. H., Najjar, A., \u0026amp; Chong, D. (2017). Neurovascular Unit Dysfunction and Blood-Brain Barrier Hyperpermeability Contribute to Schizophrenia Neurobiology: A Theoretical Integration of Clinical and Experimental Evidence. \u003cem\u003eFront Psychiatry, 8\u003c/em\u003e, 83. doi:10.3389/fpsyt.2017.00083\u003c/p\u003e\n\u003cp\u003eNajjar, S., Pearlman, D. M., Devinsky, O., Najjar, A., \u0026amp; Zagzag, D. (2013). Neurovascular unit dysfunction with blood-brain barrier hyperpermeability contributes to major depressive disorder: a review of clinical and experimental evidence. \u003cem\u003eJ Neuroinflammation, 10\u003c/em\u003e, 142. doi:10.1186/1742-2094-10-142\u003c/p\u003e\n\u003cp\u003eNguyen, T. T., Dev, S. I., Chen, G., Liou, S. C., Martin, A. S., Irwin, M. R., Carroll, J. E., Tu, X., Jeste, D. V., \u0026amp; Eyler, L. T. (2018). Abnormal levels of vascular endothelial biomarkers in schizophrenia. \u003cem\u003eEur Arch Psychiatry Clin Neurosci, 268\u003c/em\u003e(8), 849-860. doi:10.1007/s00406-017-0842-6\u003c/p\u003e\n\u003cp\u003eOrlovska-Waast, S., K\u0026ouml;hler-Forsberg, O., Brix, S. W., Nordentoft, M., Kondziella, D., Krogh, J., \u0026amp; Benros, M. E. (2019). Cerebrospinal fluid markers of inflammation and infections in schizophrenia and affective disorders: a systematic review and meta-analysis. \u003cem\u003eMolecular Psychiatry, 24\u003c/em\u003e(6), 869-887. doi:10.1038/s41380-018-0220-4\u003c/p\u003e\n\u003cp\u003ePollak, T. A., Drndarski, S., Stone, J. M., David, A. S., McGuire, P., \u0026amp; Joan Abbott, N. (2018). The blood\u0026ndash;brain barrier in psychosis. \u003cem\u003eLancet Psychiatry; 5: 79\u0026ndash;92\u003c/em\u003e.\u003c/p\u003e\n\u003cp\u003ePollak, T.A., Lennox, B.R., M\u0026uuml;ller, S., Benros ,M.E., Pr\u0026uuml;ss, H., Tebartz van Elst, L., Klein, H., Steiner, J., Frodl, T., Bogerts, B., Tian, L., Groc, L., Hasan, A., Baune, B.T., Endres, D., Haroon, E., Yolken, R., Benedetti, F., Halaris, A., Meyer, J.H., Stassen, H., Leboyer, M., Fuchs, D., Otto, M., Brown, D.A., Vincent, A., Najjar, S., Bechter, K.. Autoimmune psychosis: an international consensus on an approach to the diagnosis and management of psychosis of suspected autoimmune origin. Lancet Psychiatry. 2020 Jan;7(1):93-108. doi: 10.1016/S2215-0366(19)30290-1. Epub 2019 Oct 24.\u003c/p\u003e\n\u003cp\u003eRadu, G., Luca, C., Petrescu, L., Bordejevic, D. A., Tomescu, M. C., Andor, M., Citu, I., Mavrea, A., Buda, V., Tomescu, C., Borcan, F., \u0026amp; Dehelean, L. (2020). The Predictive Value of Endothelial Inflammatory Markers in the Onset of Schizophrenia. \u003cem\u003eNeuropsychiatr Dis Treat, 16\u003c/em\u003e, 545-555. doi:10.2147/ndt.S240349\u003c/p\u003e\n\u003cp\u003eRamos, T. N., Bullard, D. C., \u0026amp; Barnum, S. R. (2014). ICAM-1: isoforms and phenotypes. \u003cem\u003eJ Immunol, 192\u003c/em\u003e(10), 4469-4474. doi:10.4049/jimmunol.1400135\u003c/p\u003e\n\u003cp\u003eReiber, H., \u0026amp; Peter, J. B. (2001). Cerebrospinal fluid analysis: disease-related data patterns and evaluation programs. \u003cem\u003e184\u003c/em\u003e(2), 101-122. doi:10.1016/s0022-510x(00)00501-3\u003c/p\u003e\n\u003cp\u003eReiber, H., \u0026amp; Uhr, M. (2018). Physiologie des Liquors. In P. Berlit (Ed.), \u003cem\u003eKlinische Neurologie\u003c/em\u003e (pp. 1-19). Berlin, Heidelberg: Springer Berlin Heidelberg.\u003c/p\u003e\n\u003cp\u003eSchwarz, M. J., Ackenheil, M., Riedel, M., \u0026amp; M\u0026uuml;ller, N. (1998). Blood-cerebrospinal fluid barrier impairment as indicator for an immune process in schizophrenia. \u003cem\u003eNeuroscience Letters, 253\u003c/em\u003e(3), 201-203. doi:10.1016/s0304-3940(98)00655-7\u003c/p\u003e\n\u003cp\u003eSchwarz, M. J., Riedel, M., Ackenheil, M., \u0026amp; M\u0026uuml;ller, N. (2000). Decreased levels of soluble intercellular adhesion molecule-1 (sICAM-1) in unmedicated and medicated schizophrenic patients. \u003cem\u003eBiological Psychiatry, 47\u003c/em\u003e(1), 29-33. doi:10.1016/s0006-3223(99)00206-1\u003c/p\u003e\n\u003cp\u003eSerlin, Y., Shelef, I., Knyazer, B., \u0026amp; Friedman, A. (2015). Anatomy and physiology of the blood\u0026ndash;brain barrier. \u003cem\u003eSeminars in Cell \u0026amp; Developmental Biology, 38\u003c/em\u003e, 2-6. doi:10.1016/j.semcdb.2015.01.002\u003c/p\u003e\n\u003cp\u003eStefanovic, M. P., Petronijevic, N., Dunjic-Kostic, B., Velimirovic, M., Nikolic, T., Jurisic, V., Lackovic, M., Damjanovic, A., Totic-Poznanovic, S., Jovanovic, A. A., \u0026amp; Ivkovic, M. (2016). Role of sICAM-1 and sVCAM-1 as biomarkers in early and late stages of schizophrenia. \u003cem\u003eJ Psychiatr Res, 73\u003c/em\u003e, 45-52. doi:10.1016/j.jpsychires.2015.11.002\u003c/p\u003e\n\u003cp\u003eStich, O., Andres, T.A., Gross, C.M., Gerber, S.I., Rauer, S., Langosch, J.M. (2015). An observational study of inflammation in the central nervous system in patients with bipolar disorder. Bipolar Disord. 17(3):291-302. doi: 10.1111/bdi.12244. Epub 2014 Aug 11.\u003c/p\u003e\n\u003cp\u003eTumani, H., Huss, A., \u0026amp; Bachhuber, F. (2017). The cerebrospinal fluid and barriers - anatomic and physiologic considerations. \u003cem\u003eHandb Clin Neurol, 146\u003c/em\u003e, 21-32. doi:10.1016/b978-0-12-804279-3.00002-2\u003c/p\u003e\n\u003cp\u003eVaratharaj A, Galea I. The blood-brain barrier in systemic inflammation. Brain Behav Immun. 2017 Feb;60:1-12. doi: 10.1016/j.bbi.2016.03.010. Epub 2016 Mar 16.\u003c/p\u003e\n\u003cp\u003eWildemann, B., Oschmann, P., \u0026amp; Reiber, H. (2010). \u003cem\u003eLaboratory diagnosis in neurology\u003c/em\u003e (1st edition ed.). Stuttgart: Thieme.\u003c/p\u003e\n\u003cp\u003eYousef H, Czupalla CJ, Lee D, Chen MB, Burke AN, Zera KA, Zandstra J, Berber E, Lehallier B, Mathur V, Nair RV, Bonanno LN, Yang AC, Peterson T, Hadeiba H, Merkel T, K\u0026ouml;rbelin J, Schwaninger M, Buckwalter MS, Quake SR, Butcher EC, Wyss-Coray T. Aged blood impairs hippocampal neural precursor activity and activates microglia via brain endothelial cell VCAM1. Nat Med. 2019 Jun;25(6):988-1000. doi: 10.1038/s41591-019-0440-4. Epub 2019 May 13.\u003c/p\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1: Overview of findings measuring levels of sICAM-1 and sVCAM-1 in patients with schizophrenia-spectrum disorders (reviewed by M\u0026uuml;ller, 2019).\u003c/strong\u003e Abbreviations: CSF, cerebrospinal fluid; ELISA, enzyme-linked immunosorbent assay; sICAM-1, soluble intercellular adhesion molecule 1; BCSFB, blood-CSF-barrier; PCR, polymerase chain reaction; mRNA, messenger RNA; VEGF, vascular endothelial growth factor; sVCAM-1, vascular cell adhesion molecule 1; \u0026uarr;, higher; =, normal; \u0026darr;, lower; \u0026Oslash;, none.\u003c/p\u003e\n\u003ctable border=\"1\" width=\"0\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd width=\"62\"\u003e\n\u003cp\u003e\u003cstrong\u003eSample material\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"112\"\u003e\n\u003cp\u003e\u003cstrong\u003eMethod\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"95\"\u003e\n\u003cp\u003e\u003cstrong\u003eResearch group\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"97\"\u003e\n\u003cp\u003e\u003cstrong\u003eSchizophrenia-spectrum disorder group\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003e\u003cstrong\u003eControl group\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"235\"\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"62\"\u003e\n\u003cp\u003e\u003cstrong\u003eCSF\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"112\"\u003e\n\u003cp\u003eELISA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"95\"\u003e\n\u003cp\u003eSchwarz et al., 1998\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"97\"\u003e\n\u003cp\u003en=40\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003e\u0026Oslash;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"235\"\u003e\n\u003cp\u003eSignificant association of \u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;sICAM-1 and BCSFB\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"62\"\u003e\n\u003cp\u003e\u003cstrong\u003eCSF\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"112\"\u003e\n\u003cp\u003eELISA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"95\"\u003e\n\u003cp\u003eSchwarz et al., 2000\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"97\"\u003e\n\u003cp\u003en=18\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003e\u0026Oslash;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"235\"\u003e\n\u003cp\u003eSignificant positive correlation of sICAM-1 with negative symptomatology and disease duration\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"62\"\u003e\n\u003cp\u003e\u003cstrong\u003eCortex tissue\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"112\"\u003e\n\u003cp\u003ePCR\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"95\"\u003e\n\u003cp\u003eCai et al., 2018\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"97\"\u003e\n\u003cp\u003en=37\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003en=37\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"235\"\u003e\n\u003cp\u003e\u0026uarr; expression of ICAM-1 mRNA\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"62\"\u003e\n\u003cp\u003e\u003cstrong\u003ePlasma\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"112\"\u003e\n\u003cp\u003eMultiplexing immuneassay (Luminex\u0026reg;)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"95\"\u003e\n\u003cp\u003eCai et al., 2018\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"97\"\u003e\n\u003cp\u003en=78\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003en=73\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"235\"\u003e\n\u003cp\u003e\u0026uarr; levels of sICAM-1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"62\"\u003e\n\u003cp\u003e\u003cstrong\u003ePlasma\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"112\"\u003e\n\u003cp\u003eMultiplexing immuneassay (Meso Scale Discovery MULTI-SPOT\u0026reg;)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"95\"\u003e\n\u003cp\u003eNguyen et al., 2018\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"97\"\u003e\n\u003cp\u003en=134\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003en=113\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"235\"\u003e\n\u003cp\u003e\u0026uarr; levels of \u0026lsquo;vascular endothelial index\u0026rsquo; including VEGF, sICAM-1, sVCAM-1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"62\"\u003e\n\u003cp\u003e\u003cstrong\u003eSerum\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"112\"\u003e\n\u003cp\u003eELISA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"95\"\u003e\n\u003cp\u003eSchwarz et al., 2000\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"97\"\u003e\n\u003cp\u003en=72\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003en=38\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"235\"\u003e\n\u003cp\u003e\u0026darr; levels of sICAM-1 and increase of sICAM-1 during treatment\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"62\"\u003e\n\u003cp\u003e\u003cstrong\u003eSerum\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"112\"\u003e\n\u003cp\u003eELISA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"95\"\u003e\n\u003cp\u003eKroenig et al., 2005\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"97\"\u003e\n\u003cp\u003en=70\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003en=128\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"235\"\u003e\n\u003cp\u003e\u0026darr; levels of sICAM-1 and relationship to ICAM-1 G214A polymorphism\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"62\"\u003e\n\u003cp\u003e\u003cstrong\u003eSerum\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"112\"\u003e\n\u003cp\u003eELISA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"95\"\u003e\n\u003cp\u003eStefanovic et al., 2016\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"97\"\u003e\n\u003cp\u003en=80\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003en=80\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"235\"\u003e\n\u003cp\u003e= levels of sICAM-1 in early-stage, \u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026uarr; levels of sICAM-1 in late-stage and associations with severity and disease duration\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2: Clinical data of patients with schizophrenia-spectrum disorder and depressive disorder. \u003c/strong\u003eAbbreviations: CSF = cerebrospinal fluid, MRI = magnetic resonance imaging, EEG = electroencephalography, F = female, M = male, SD = standard deviation, SSRI = selective serotonin reuptake inhibitor, SSNRI = selective serotonin/noradrenaline reuptake inhibitor.\u003c/p\u003e\n\u003ctable border=\"1\" width=\"0\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd width=\"225\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"236\"\u003e\n\u003cp\u003e\u003cstrong\u003eSchizophrenia-spectrum disorder (N=40)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"217\"\u003e\n\u003cp\u003e\u003cstrong\u003eDepressive disorder (N=39)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"225\"\u003e\n\u003cp\u003e\u003cstrong\u003eSex\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"236\"\u003e\n\u003cp\u003e16 M : 24 F\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"217\"\u003e\n\u003cp\u003e14 M : 25 F\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"225\"\u003e\n\u003cp\u003e\u003cstrong\u003eAge\u003c/strong\u003e (Mean\u0026plusmn;SD, range)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"236\"\u003e\n\u003cp\u003e33.63 \u0026plusmn; 13.38\u003c/p\u003e\n\u003cp\u003e(18-65years)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"217\"\u003e\n\u003cp\u003e32.54 \u0026plusmn; 7.65\u003c/p\u003e\n\u003cp\u003e(18-44 years)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"3\" width=\"678\"\u003e\n\u003cp\u003e\u003cstrong\u003eClinical syndrome and characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"225\"\u003e\n\u003cp\u003eSevere depressive episode\u003c/p\u003e\n\u003cp\u003eWith psychotic symptoms\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Without psychotic symptoms\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSchizophrenia spectrum disorder\u003c/p\u003e\n\u003cp\u003eParanoid-hallucinatory\u003c/p\u003e\n\u003cp\u003eHebephrenic\u003c/p\u003e\n\u003cp\u003eCatatonic\u003c/p\u003e\n\u003cp\u003eDelusional disorders\u003c/p\u003e\n\u003cp\u003eSchizoaffective\u003c/p\u003e\n\u003cp\u003e- Depressive\u003c/p\u003e\n\u003cp\u003e- Manic\u003c/p\u003e\n\u003cp\u003e- Mixed\u003c/p\u003e\n\u003cp\u003eAcute polymorphic psychotic\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"236\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e40 (100%)\u003c/p\u003e\n\u003cp\u003e25 (63%)\u003c/p\u003e\n\u003cp\u003e1 (3%)\u003c/p\u003e\n\u003cp\u003e1 (3%)\u003c/p\u003e\n\u003cp\u003e1 (3%)\u003c/p\u003e\n\u003cp\u003e11 (28%)\u003c/p\u003e\n\u003cp\u003e6 (15%)\u003c/p\u003e\n\u003cp\u003e3 (8%)\u003c/p\u003e\n\u003cp\u003e2 (5%)\u003c/p\u003e\n\u003cp\u003e1 (3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"217\"\u003e\n\u003cp\u003e39 (100%)\u003c/p\u003e\n\u003cp\u003e7 (18%)\u003c/p\u003e\n\u003cp\u003e32 (82%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"225\"\u003e\n\u003cp\u003e\u003cstrong\u003eCourse of disease\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRecurrent/chronic\u003c/p\u003e\n\u003cp\u003eFirst episode\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"236\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e27 (68%)\u003c/p\u003e\n\u003cp\u003e13 (33%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"217\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;27 (69%)\u003c/p\u003e\n\u003cp\u003e12 (31%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"225\"\u003e\n\u003cp\u003e\u003cstrong\u003eNeurologic comorbidity\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSeizures/Attacks\u003c/p\u003e\n\u003cp\u003eTraumatic\u003c/p\u003e\n\u003cp\u003ePolyneuropathy\u003c/p\u003e\n\u003cp\u003eMigraine/Headache\u003c/p\u003e\n\u003cp\u003eOverall\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"236\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e2 (5%)\u003c/p\u003e\n\u003cp\u003e3 (8%)\u003c/p\u003e\n\u003cp\u003e0 (0%)\u003c/p\u003e\n\u003cp\u003e1 (3%)\u003c/p\u003e\n\u003cp\u003e6 (15%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"217\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e0 (0%)\u003c/p\u003e\n\u003cp\u003e0 (0%)\u003c/p\u003e\n\u003cp\u003e0 (0%)\u003c/p\u003e\n\u003cp\u003e1 (3%)\u003c/p\u003e\n\u003cp\u003e1 (3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"225\"\u003e\n\u003cp\u003e\u003cstrong\u003ePsychotropic medication \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eat the time of sampling\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSSRI\u003c/p\u003e\n\u003cp\u003eSSNRI\u003c/p\u003e\n\u003cp\u003eTricyclic antidepressants\u003c/p\u003e\n\u003cp\u003eBupropion\u003c/p\u003e\n\u003cp\u003eMirtazapine\u003c/p\u003e\n\u003cp\u003eTypical neuroleptics\u003c/p\u003e\n\u003cp\u003eAtypical neuroleptics\u003c/p\u003e\n\u003cp\u003eLithium\u003c/p\u003e\n\u003cp\u003eAnticonvulsant\u003c/p\u003e\n\u003cp\u003eBenzodiazepine\u003c/p\u003e\n\u003cp\u003eUnmedicated\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"236\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e4 (10%)\u003c/p\u003e\n\u003cp\u003e1 (3%)\u003c/p\u003e\n\u003cp\u003e0 (0%)\u003c/p\u003e\n\u003cp\u003e4 (10%)\u003c/p\u003e\n\u003cp\u003e1 (3%)\u003c/p\u003e\n\u003cp\u003e9 (23%)\u003c/p\u003e\n\u003cp\u003e40 (100%)\u003c/p\u003e\n\u003cp\u003e7 (18%)\u003c/p\u003e\n\u003cp\u003e7 (18%)\u003c/p\u003e\n\u003cp\u003e9 (23%)\u003c/p\u003e\n\u003cp\u003e0 (0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"217\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e9 (23%)\u003c/p\u003e\n\u003cp\u003e21 (54%)\u003c/p\u003e\n\u003cp\u003e8 (21%)\u003c/p\u003e\n\u003cp\u003e4 (10%)\u003c/p\u003e\n\u003cp\u003e6 (15%)\u003c/p\u003e\n\u003cp\u003e4 (10%)\u003c/p\u003e\n\u003cp\u003e21 (54%)\u003c/p\u003e\n\u003cp\u003e9 (23%)\u003c/p\u003e\n\u003cp\u003e1 (3%)\u003c/p\u003e\n\u003cp\u003e3 (8%)\u003c/p\u003e\n\u003cp\u003e2 (5%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3: Demographic data. \u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" width=\"0\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd width=\"225\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"236\"\u003e\n\u003cp\u003e\u003cstrong\u003eSchizophrenia-spectrum disorder (N=40)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"217\"\u003e\n\u003cp\u003e\u003cstrong\u003eDepressive disorder (N=39)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"225\"\u003e\n\u003cp\u003e\u003cstrong\u003eMarital status\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSingle\u003c/p\u003e\n\u003cp\u003eMarried\u003c/p\u003e\n\u003cp\u003eDivorced\u003c/p\u003e\n\u003cp\u003eWidowed\u003c/p\u003e\n\u003cp\u003eUnknown\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"236\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e30 (77%)\u003c/p\u003e\n\u003cp\u003e6 (15%)\u003c/p\u003e\n\u003cp\u003e1 (3%)\u003c/p\u003e\n\u003cp\u003e1 (3%)\u003c/p\u003e\n\u003cp\u003e2 (5%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"217\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e31 (79%)\u003c/p\u003e\n\u003cp\u003e6 (15%)\u003c/p\u003e\n\u003cp\u003e2 (5%)\u003c/p\u003e\n\u003cp\u003e0 (0%)\u003c/p\u003e\n\u003cp\u003e0 (0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"225\"\u003e\n\u003cp\u003e\u003cstrong\u003eLevel of education\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLow\u003c/p\u003e\n\u003cp\u003eMiddle\u003c/p\u003e\n\u003cp\u003eHigh\u003c/p\u003e\n\u003cp\u003eUnknown\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"236\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e11 (28%)\u003c/p\u003e\n\u003cp\u003e7 (18%)\u003c/p\u003e\n\u003cp\u003e19 (48%)\u003c/p\u003e\n\u003cp\u003e3 (8%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"217\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e2 (5%)\u003c/p\u003e\n\u003cp\u003e8 (21%)\u003c/p\u003e\n\u003cp\u003e28 (72%)\u003c/p\u003e\n\u003cp\u003e1 (3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"225\"\u003e\n\u003cp\u003e\u003cstrong\u003eWork situation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eUnemployed\u003c/p\u003e\n\u003cp\u003eWorking\u003c/p\u003e\n\u003cp\u003eIn training\u003c/p\u003e\n\u003cp\u003eRetired\u003c/p\u003e\n\u003cp\u003eHousewife/-man\u003c/p\u003e\n\u003cp\u003eUnknown\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"236\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e7 (18%)\u003c/p\u003e\n\u003cp\u003e13 (33%)\u003c/p\u003e\n\u003cp\u003e11 (28%)\u003c/p\u003e\n\u003cp\u003e6 (15%)\u003c/p\u003e\n\u003cp\u003e2 (5%)\u003c/p\u003e\n\u003cp\u003e1 (3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"217\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e6 (15%)\u003c/p\u003e\n\u003cp\u003e20 (51%)\u003c/p\u003e\n\u003cp\u003e11 (28%)\u003c/p\u003e\n\u003cp\u003e1 (3%)\u003c/p\u003e\n\u003cp\u003e1 (3%)\u003c/p\u003e\n\u003cp\u003e0 (0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"225\"\u003e\n\u003cp\u003e\u003cstrong\u003eHousing situation \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAlone\u003c/p\u003e\n\u003cp\u003eWith partner/family\u003c/p\u003e\n\u003cp\u003eWith parents/guardian\u003c/p\u003e\n\u003cp\u003eOther\u003c/p\u003e\n\u003cp\u003eUnknown\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"236\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e13 (33%)\u003c/p\u003e\n\u003cp\u003e11 (28%)\u003c/p\u003e\n\u003cp\u003e12 (30%)\u003c/p\u003e\n\u003cp\u003e4 (10%)\u003c/p\u003e\n\u003cp\u003e0 (0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"217\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e18 (47%)\u003c/p\u003e\n\u003cp\u003e10 (26%)\u003c/p\u003e\n\u003cp\u003e10 (26%)\u003c/p\u003e\n\u003cp\u003e0 (0%)\u003c/p\u003e\n\u003cp\u003e1 (3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"225\"\u003e\n\u003cp\u003e\u003cstrong\u003eSuicide attempts\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003cp\u003eOne\u003c/p\u003e\n\u003cp\u003eTwo\u003c/p\u003e\n\u003cp\u003eThree\u003c/p\u003e\n\u003cp\u003eFour\u003c/p\u003e\n\u003cp\u003eFive\u003c/p\u003e\n\u003cp\u003eSix\u003c/p\u003e\n\u003cp\u003eUnclear\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"236\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e28 (70%)\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; 2 (5%)\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; 4 (10%)\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; 1 (3%)\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; 1 (3%)\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; 1 (3%)\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; \u0026nbsp;0 (0%)\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; \u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;3 (8%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"217\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e34 (87%)\u003c/p\u003e\n\u003cp\u003e2 (5%)\u003c/p\u003e\n\u003cp\u003e2 (5%)\u003c/p\u003e\n\u003cp\u003e0 (0%)\u003c/p\u003e\n\u003cp\u003e0 (0%)\u003c/p\u003e\n\u003cp\u003e0 (0%)\u003c/p\u003e\n\u003cp\u003e1 (3%)\u003c/p\u003e\n\u003cp\u003e0 (0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"225\"\u003e\n\u003cp\u003e\u003cstrong\u003eNumber of earlier inpatient\u003c/strong\u003e \u003cstrong\u003etreatments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003cp\u003eOne\u003c/p\u003e\n\u003cp\u003eTwo\u003c/p\u003e\n\u003cp\u003eThree\u003c/p\u003e\n\u003cp\u003eFour\u003c/p\u003e\n\u003cp\u003eFive\u003c/p\u003e\n\u003cp\u003e\u0026gt; Five\u003c/p\u003e\n\u003cp\u003eUnclear\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"236\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e12 (30%)\u003c/p\u003e\n\u003cp\u003e6 (15%)\u003c/p\u003e\n\u003cp\u003e3 (8%)\u003c/p\u003e\n\u003cp\u003e3 (8%)\u003c/p\u003e\n\u003cp\u003e2 (5%)\u003c/p\u003e\n\u003cp\u003e5 (13%)\u003c/p\u003e\n\u003cp\u003e7 (18%)\u003c/p\u003e\n\u003cp\u003e2 (5%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"217\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e15 (38%)\u003c/p\u003e\n\u003cp\u003e12 (31%)\u003c/p\u003e\n\u003cp\u003e6 (15%)\u003c/p\u003e\n\u003cp\u003e2 (5%)\u003c/p\u003e\n\u003cp\u003e1 (3%)\u003c/p\u003e\n\u003cp\u003e2 (5%)\u003c/p\u003e\n\u003cp\u003e1 (3%)\u003c/p\u003e\n\u003cp\u003e0 (0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4: Cell adhesion molecule levels in the cerebrospinal fluid.\u003c/strong\u003e Abbreviations: PAI-1 = plasminogen activator inhibitor 1, SD = standard deviation, s-ICAM-1 = soluble intercellular adhesion molecule-1, sVCAM-1 = soluble vascular cell adhesion molecule-1.\u003c/p\u003e\n\u003ctable border=\"1\" width=\"0\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd width=\"147\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"151\"\u003e\n\u003cp\u003e\u003cstrong\u003eSchizophrenia-spectrum disorder (N=40)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"151\"\u003e\n\u003cp\u003e\u003cstrong\u003eDepressive disorder (N=39)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"142\"\u003e\n\u003cp\u003e\u003cstrong\u003eStatistics\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"147\"\u003e\n\u003cp\u003e\u003cstrong\u003ePAI-1 (pg/ml)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(Mean \u0026plusmn; SD)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"151\"\u003e\n\u003cp\u003e72.006 \u0026plusmn; 46.810\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"151\"\u003e\n\u003cp\u003e30.756 \u0026plusmn; 23.397\u0026nbsp; (N=38)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"142\"\u003e\n\u003cp\u003e\u003cstrong\u003eF= 13.312\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ep\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"147\"\u003e\n\u003cp\u003e\u003cstrong\u003esICAM-1 (pg/ml)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(Mean \u0026plusmn; SD)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"151\"\u003e\n\u003cp\u003e1196.252 \u0026plusmn; 768.714\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"151\"\u003e\n\u003cp\u003e466.205 \u0026plusmn; 277.053\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"142\"\u003e\n\u003cp\u003e\u003cstrong\u003eF=12.716\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ep\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"147\"\u003e\n\u003cp\u003e\u003cstrong\u003esVCAM-1 (pg/ml)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(Mean \u0026plusmn; SD)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"151\"\u003e\n\u003cp\u003e456.197 \u0026plusmn; 155.549\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"151\"\u003e\n\u003cp\u003e234.195 \u0026plusmn; 151.553\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"142\"\u003e\n\u003cp\u003e\u003cstrong\u003eF=0.239\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ep\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eTable 5: Findings in cerebrospinal fluid routine diagnostics.\u003c/strong\u003e\u0026nbsp; Abbreviations: WBC = white blood cell, SD = standard deviation, y. = years, IgG = immunoglobulin G, CSF = cerebrospinal fluid, OCBs = oligoclonal bands. * Two findings were borderline positive: A first patient had some weak identical bands in CSF and serum, a second patient had an isolated OCB in the CSF.\u003c/p\u003e\n\u003ctable border=\"1\" width=\"0\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd width=\"144\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"110\"\u003e\n\u003cp\u003e\u003cstrong\u003eReference\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"115\"\u003e\n\u003cp\u003e\u003cstrong\u003eSchizophrenia-spectrum disorder (N=40)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e\u003cstrong\u003eDepressive disorder (N=39)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"115\"\u003e\n\u003cp\u003e\u003cstrong\u003eStatistics\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"144\"\u003e\n\u003cp\u003e\u003cstrong\u003eWBC counts\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(Mean \u0026plusmn; SD)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"110\"\u003e\n\u003cp\u003ein /\u0026micro;l\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"115\"\u003e\n\u003cp\u003e1.85 \u0026plusmn; 1.46\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e1.82 \u0026plusmn; 1.23\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"115\"\u003e\n\u003cp\u003eF=0.066\u003c/p\u003e\n\u003cp\u003ep=0.923\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"144\"\u003e\n\u003cp\u003e\u003cstrong\u003eNumber of increased WBC counts\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"110\"\u003e\n\u003cp\u003e\u0026lt; 5 /\u0026micro;l\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"115\"\u003e\n\u003cp\u003e\u0026uarr;: 3 (8%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e\u0026uarr;: 2 (5%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"115\"\u003e\n\u003cp\u003eChi\u003csup\u003e2\u003c/sup\u003e=0.187\u003c/p\u003e\n\u003cp\u003ep=0.665\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"144\"\u003e\n\u003cp\u003e\u003cstrong\u003eProtein concentration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(Mean \u0026plusmn; SD)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"110\"\u003e\n\u003cp\u003ein mg/l\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"115\"\u003e\n\u003cp\u003e406.45 \u0026plusmn; 196.15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e418.87 \u0026plusmn; 153.68\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"115\"\u003e\n\u003cp\u003eF=0.599\u003c/p\u003e\n\u003cp\u003ep=0.755\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"144\"\u003e\n\u003cp\u003e\u003cstrong\u003eNumber of increased protein concentration\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"110\"\u003e\n\u003cp\u003e\u0026nbsp;\u0026lt; 450 mg/l\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"115\"\u003e\n\u003cp\u003e\u0026uarr;: 12 (30%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e\u0026uarr;: 14 (36%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"115\"\u003e\n\u003cp\u003eChi\u003csup\u003e2\u003c/sup\u003e=0.311\u003c/p\u003e\n\u003cp\u003ep=0.577\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"144\"\u003e\n\u003cp\u003e\u003cstrong\u003eAlbumin quotient \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(Mean \u0026plusmn; SD)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"110\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"115\"\u003e\n\u003cp\u003e5.02 \u0026plusmn; 2.29\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e5.12 \u0026plusmn; 2.05\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"115\"\u003e\n\u003cp\u003eF=0.158\u003c/p\u003e\n\u003cp\u003ep=0.834\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"144\"\u003e\n\u003cp\u003e\u003cstrong\u003eNumber of increased albumin quotients\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"110\"\u003e\n\u003cp\u003e\u0026lt;40y.: \u0026lt; 6.5 x 10\u003csup\u003e-3\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e40-60y.: \u0026lt; 8 x 10\u003csup\u003e-3 \u003c/sup\u003e\u0026gt;60y.: \u0026lt; 9.3 x 10\u003csup\u003e-3\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"115\"\u003e\n\u003cp\u003e\u0026uarr;: 6 (15%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e\u0026uarr;: 8 (21%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"115\"\u003e\n\u003cp\u003eChi\u003csup\u003e2\u003c/sup\u003e=0.412\u003c/p\u003e\n\u003cp\u003ep=0.521\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"144\"\u003e\n\u003cp\u003e\u003cstrong\u003eIgG-Index\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(Mean \u0026plusmn; SD)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"110\"\u003e\n\u003cp\u003ein mg/l\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"115\"\u003e\n\u003cp\u003e0.49 \u0026plusmn; 0.04\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e0.49 \u0026plusmn; 0.09\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"115\"\u003e\n\u003cp\u003eF=1.813\u003c/p\u003e\n\u003cp\u003ep=0.731\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"144\"\u003e\n\u003cp\u003e\u003cstrong\u003eNumber of increased IgG indices\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"110\"\u003e\n\u003cp\u003e\u0026lt; 0.7 mg/l\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"115\"\u003e\n\u003cp\u003e\u0026uarr;: 0 (0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e\u0026uarr;: 1 (3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"115\"\u003e\n\u003cp\u003eChi\u003csup\u003e2\u003c/sup\u003e=1.039\u003c/p\u003e\n\u003cp\u003ep=0.308\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"144\"\u003e\n\u003cp\u003e\u003cstrong\u003eOCBs in CSF\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"110\"\u003e\n\u003cp\u003enegative\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"115\"\u003e\n\u003cp\u003e1* (3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e2 (5%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"115\"\u003e\n\u003cp\u003eChi\u003csup\u003e2\u003c/sup\u003e=0.556\u003c/p\u003e\n\u003cp\u003ep=0.346\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"ICAM-1, VCAM-1, schizophrenia, depression, neuroinflammation, blood–brain barrier, cerebrospinal fluid","lastPublishedDoi":"10.21203/rs.3.rs-121960/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-121960/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eIntroduction\u003c/p\u003e\u003cp\u003eImmunological explanatory approaches are becoming increasingly important in schizophrenia research. In this context, the function of the blood–brain barrier (BBB) and the blood–cerebrospinal fluid (CSF) barrier (BCSFB) play an essential role. Different adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), are key elements in sustaining the integrity of the BBB and BCSFB. The objectives of this study were (1) to compare the levels of different cell adhesion molecules in the CSF of patients with schizophrenia spectrum disorders to those of patients with unipolar depression and (2) to analyze their association with the established markers of the BBB/BCSFB function (total protein and albumin quotient [AQ]).\u003c/p\u003e\u003cp\u003ePatients and methods\u003c/p\u003e\u003cp\u003eA total of 40 patients with schizophrenia spectrum disorder and 39 age- and sex-matched control patients with unipolar depression were analyzed. The levels of soluble ICAM-1 (s-ICAM-1), soluble VCAM-1 (s-VCAM-1), and plasminogen activator inhibitor 1 (PAI-1) in the CSF were measured using a magnetic bead multiplexing immunoassay.\u003c/p\u003e\u003cp\u003eResults\u003c/p\u003e\u003cp\u003eThe levels of sICAM-1 (p\u0026lt;0.001), sVCAM-1 (p\u0026lt;0.001), and PAI-1 (p\u0026lt;0.001) in the CSF were significantly higher in patients with schizophrenia spectrum disorder than in patients with unipolar depression. Correlation analyses revealed a significant correlation of protein concentrations with sVCAM-1 levels (r=0.505, p=0.001) and of AQs with the sVCAM-1 (r=0.583, p\u0026lt;0.001) and PAI-1 (r=0.337, p=0.033) levels in patients with schizophrenia.\u003c/p\u003e\u003cp\u003eLimitation\u003c/p\u003e\u003cp\u003eThe significance of the study is limited by the retrospective research design and by the absence of a healthy control group. The assay used was not previously established for the measurement of CSF.\u003c/p\u003e\u003cp\u003eDiscussion\u003c/p\u003e\u003cp\u003eResults revealed that sICAM-1 and sVCAM-1 levels in the CSF are higher in patients with schizophrenia spectrum disorder than in patients with depression. These circulating signaling molecules may indicate endothelial dysfunction causing impaired BBB/BCSFB function in patients with schizophrenia spectrum disorders. Consistent with this view, a highly significant correlation of sVCAM-1 with CSF protein and AQs was detected. Upregulation of these cell adhesion molecules might be indicative of a proinflammatory immune response underlying the BBB/BCSFB disturbance in a subgroup of patients with schizophrenia spectrum disorders. Further translational and controlled studies on the role of different cell adhesion molecules in schizophrenia are needed.\u003c/p\u003e","manuscriptTitle":"Upregulation of sICAM-1 and sVCAM-1 Levels in the Cerebrospinal Fluid of Patients with Schizophrenia Spectrum Disorders","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2020-12-28 16:31:30","doi":"10.21203/rs.3.rs-121960/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f233620b-66b3-4e35-864e-5c29f73f86db","owner":[],"postedDate":"December 28th, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":1616273,"name":"Psychiatry"}],"tags":[],"updatedAt":"2024-07-14T13:20:28+00:00","versionOfRecord":{"articleIdentity":"rs-121960","link":"https://doi.org/10.3390/diagnostics11071134","journal":{"identity":"diagnostics","isVorOnly":true,"title":"Diagnostics"},"publishedOn":"2021-06-22 13:20:28","publishedOnDateReadable":"June 22nd, 2021"},"versionCreatedAt":"2020-12-28 16:31:30","video":"","vorDoi":"10.3390/diagnostics11071134","vorDoiUrl":"https://doi.org/10.3390/diagnostics11071134","workflowStages":[]},"version":"v1","identity":"rs-121960","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-121960","identity":"rs-121960","version":["v1"]},"buildId":"ehx78VzkSd0WSzXnipQa-","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}