{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T09:50:00Z","timestamp":1766137800585,"version":"3.37.3"},"reference-count":67,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2021,9,29]],"date-time":"2021-09-29T00:00:00Z","timestamp":1632873600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004836","name":"Det Frie Forskningsr\u00e5d","doi-asserted-by":"publisher","award":["7025-0078B"],"award-info":[{"award-number":["7025-0078B"]}],"id":[{"id":"10.13039\/501100004836","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003554","name":"Lundbeckfonden","doi-asserted-by":"publisher","award":["R268-2016-3925"],"award-info":[{"award-number":["R268-2016-3925"]}],"id":[{"id":"10.13039\/501100003554","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Psykiatrisk Forskningsfond af 1967"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\"><jats:title>Background<\/jats:title><jats:p>Though many previous studies have indicated immunological alterations in psychotic disorders, the role and prevalence of neuroinflammation is still unknown. Studies previously investigating immune related biomarkers in the cerebrospinal fluid (CSF) of these patients are mainly small studies on few markers, and many have not compared patients to healthy controls.<\/jats:p><\/jats:sec><jats:sec id=\"sec002\"><jats:title>Methods<\/jats:title><jats:p>We will conduct a large case-control study including at least 100 patients with recent onset psychotic disorders and 100 sex- and age matched healthy controls. The cases will include patients diagnosed with a psychotic disorder according to ICD-10 (F20\/F22-29) within a year prior to inclusion. We will collect both CSF, blood and fecal samples, to gain insight into possible immunological alterations. The psychopathology of all participants will thoroughly be evaluated using the SCAN interview, and multiple rating scales covering different symptom groups. All participants will partake in a detailed neurological examination, including the Neurological Evaluation Scale assessing neurological soft signs. Additionally, we will assess cognitive functioning, evaluate quality of life and level of functioning, and collect data on a broad array of possible confounders. Our primary outcomes will include CSF leucocytes, CSF\/serum albumin ratio, CSF total protein, IgG index, CSF levels of IL-6 and IL-8, and presence of antineuronal autoantibodies in CSF and blood. For our secondary outcomes, exploratory analyses will be performed on a broader panel of neuroimmunological markers. All participants will be invited for a follow-up visit to assess longitudinal changes. The current study is part of a larger CSF biobank build-up for severe mental disorders (PSYCH-FLAME).<\/jats:p><\/jats:sec><jats:sec id=\"sec003\"><jats:title>Discussion<\/jats:title><jats:p>This study will represent the largest investigation of CSF in patients with psychotic disorders compared to healthy controls to date. We expect the study to contribute with new, important knowledge on pathophysiological mechanisms, and to help pave the way for future investigations of individualized treatment options.<\/jats:p><\/jats:sec><jats:sec id=\"sec004\"><jats:title>Trial registration<\/jats:title><jats:p>The study is approved by The Regional Committee on Health Research Ethics (Capital Region, j.no: H-16030985) and The Danish Data Protection Agency (j.no: RHP-2016-020, I-Suite no.: 04945).<\/jats:p><\/jats:sec>","DOI":"10.1371\/journal.pone.0257946","type":"journal-article","created":{"date-parts":[[2021,9,29]],"date-time":"2021-09-29T18:54:06Z","timestamp":1632941646000},"page":"e0257946","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":9,"title":["Immunological investigations of the cerebrospinal fluid in patients with recent onset psychotic disorders: A study protocol"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9984-2202","authenticated-orcid":true,"given":"Rose","family":"Jeppesen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sonja","family":"Orlovska-Waast","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nina","family":"Vindegaard S\u00f8rensen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rune Haubo Bojesen","family":"Christensen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael Eriksen","family":"Benros","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,9,29]]},"reference":[{"key":"pone.0257946.ref001","first-page":"25","volume-title":"The Societal Cost of Schizophrenia: A Systematic Review. PharmacoEconomics","author":"H Jin","year":"2017"},{"key":"pone.0257946.ref002","doi-asserted-by":"crossref","first-page":"1981","DOI":"10.1017\/S0033291717000435","article-title":"Antipsychotic treatment resistance in first-episode psychosis: prevalence, subtypes and predictors","volume":"47","author":"A Demjaha","year":"2017","journal-title":"Psychol Med"},{"key":"pone.0257946.ref003","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.schres.2012.01.014","article-title":"Treatment response trajectories and antipsychotic medications: Examination of up to 18months of treatment in the CATIE chronic schizophrenia trial","volume":"137","author":"SZ Levine","year":"2012","journal-title":"Schizophr Res"},{"key":"pone.0257946.ref004","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1016\/j.euroneuro.2014.03.001","article-title":"Effect of antipsychotic medication on overall life satisfaction among individuals with chronic schizophrenia: Findings from the NIMH CATIE study","volume":"24","author":"G Fervaha","year":"2014","journal-title":"Eur Neuropsychopharmacol."},{"key":"pone.0257946.ref005","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1111\/j.1600-0447.2007.00992.x","article-title":"Pharmacological treatment of negative symptoms of schizophrenia: therapeutic opportunity or Cul-de-sac?","volume":"115","author":"PF Buckley","year":"2007","journal-title":"Acta Psychiatr Scand"},{"key":"pone.0257946.ref006","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1007\/s00406-015-0596-y","article-title":"Pharmacological treatment of negative symptoms in schizophrenia","volume":"265","author":"H-J M\u00f6ller","year":"2015","journal-title":"Eur Arch Psychiatry Clin Neurosci"},{"key":"pone.0257946.ref007","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1001\/archpsyc.64.6.633","article-title":"Neurocognitive Effects of Antipsychotic Medications in Patients With Chronic Schizophrenia in the CATIE Trial","volume":"64","author":"RSE Keefe","year":"2007","journal-title":"Arch Gen Psychiatry"},{"key":"pone.0257946.ref008","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1007\/s40263-013-0047-0","article-title":"Can Antipsychotics Improve Social Cognition in Patients with Schizophrenia?","volume":"27","author":"K Kucharska-Pietura","year":"2013","journal-title":"CNS Drugs"},{"key":"pone.0257946.ref009","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1016\/j.eurpsy.2014.01.007","article-title":"Impact of primary negative symptoms on functional outcomes in schizophrenia.","volume":"29","author":"G Fervaha","year":"2014","journal-title":"Eur Psychiatry"},{"key":"pone.0257946.ref010","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1007\/s11136-007-9195-3","article-title":"Predicting quality of life impairment in chronic schizophrenia from cognitive variables","volume":"16","author":"MS Ritsner","year":"2007","journal-title":"Qual Life 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Jeppesen","year":"2020"},{"key":"pone.0257946.ref018","article-title":"Cerebrospinal fluid markers of inflammation and infections in schizophrenia and affective disorders: a systematic review and meta-analysis","author":"S Orlovska-Waast","year":"2018","journal-title":"Mol Psychiatry"},{"key":"pone.0257946.ref019","first-page":"8","article-title":"Red flags: Clinical signs for identifying autoimmune encephalitis in psychiatric patients","author":"J Herken","year":"2017","journal-title":"Front Psychiatry"},{"key":"pone.0257946.ref020","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/S1474-4422(12)70310-1","article-title":"Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: An observational cohort study","volume":"12","author":"MJ Titulaer","year":"2013","journal-title":"Lancet Neurol"},{"key":"pone.0257946.ref021","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1016\/j.bbrc.2018.02.131","article-title":"Increased cerebrospinal fluid complement C5 levels in major depressive disorder and schizophrenia","volume":"497","author":"T Ishii","year":"2018","journal-title":"Biochem Biophys Res Commun"},{"key":"pone.0257946.ref022","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1093\/ijnp\/pyaa049","article-title":"Increased Matrix Metalloproteinases in Cerebrospinal Fluids of Patients with Major Depressive Disorder and Schizophrenia","volume":"23","author":"W Omori","year":"2020","journal-title":"Int J Neuropsychopharmacol"},{"key":"pone.0257946.ref023","doi-asserted-by":"crossref","first-page":"2475","DOI":"10.1017\/S003329171300295X","article-title":"receptor antibodies in patients with schizophrenia and related psychoses: a systematic review and meta-analysis","volume":"44","author":"TA Pollak","year":"2014","journal-title":"Psychol 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Hamilton","year":"1960","journal-title":"J Neurol Neurosurg Psychiat"},{"key":"pone.0257946.ref032","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1192\/bjp.134.4.382","article-title":"A new depression scale designed to be sensitive to change","volume":"134","author":"SA Montgomery","year":"1979","journal-title":"Br J Psychiatry"},{"key":"pone.0257946.ref033","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1111\/j.2044-8341.1959.tb00467.x","article-title":"The assessment of anxiety states by rating","volume":"32","author":"M. Hamilton","year":"1959","journal-title":"Br J Med Psychol"},{"key":"pone.0257946.ref034","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1192\/bjp.133.5.429","article-title":"A rating scale for mania: Reliability, validity and sensitivity","volume":"133","author":"RC Young","year":"1978","journal-title":"Br J Psychiatry"},{"key":"pone.0257946.ref035","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1111\/j.1600-0447.2000.tb10933.x","article-title":"Development, reliability and acceptability of a new version of the DSM- IV Social Occupational Functioning Assessment Scale (SOFAS) to assess routine social functioning","volume":"101","author":"PL Morosini","year":"2000","journal-title":"Acta Psychiatr Scand."},{"key":"pone.0257946.ref036","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/1744-859X-10-2","article-title":"Guidelines for rating Global Assessment of Functioning (GAF).","author":"IM Aas","year":"2011","journal-title":"Annals of General Psychiatry. BioMed Central"},{"key":"pone.0257946.ref037","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/S0165-0327(00)00309-8","article-title":"The sensitivity and specificity of the Major Depression Inventory, using the Present State Examination as the index of diagnostic validity","volume":"66","author":"P Bech","year":"2001","journal-title":"J Affect Disord"},{"key":"pone.0257946.ref038","doi-asserted-by":"crossref","first-page":"1727","DOI":"10.1007\/s11136-011-9903-x","article-title":"Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L)","volume":"20","author":"M Herdman","year":"2011","journal-title":"Qual Life Res."},{"journal-title":"The Brief Assessment of Cognition in Schizophrenia: reliability, sensitivity, and comparison with a standard neurocognitive battery","author":"RSE Keefe","key":"pone.0257946.ref039"},{"key":"pone.0257946.ref040","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1111\/j.1532-5415.2005.53221.x","article-title":"The Montreal Cognitive Assessment, MoCA: A brief screening tool for mild cognitive impairment","volume":"53","author":"ZS Nasreddine","year":"2005","journal-title":"J Am Geriatr Soc."},{"key":"pone.0257946.ref041","first-page":"189","article-title":"\u2018Mini-mental state\u2019. A practical method for grading the cognitive state of patients for the clinician","volume":"12","author":"MF Folstein","year":"1975","journal-title":"J Psychiatr Res"},{"key":"pone.0257946.ref042","doi-asserted-by":"crossref","first-page":"2277","DOI":"10.1038\/nprot.2006.390","article-title":"Administration and interpretation of the Trail Making Test","volume":"1","author":"CR Bowie","year":"2006","journal-title":"Nat Protoc."},{"key":"pone.0257946.ref043","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/0165-1781(89)90148-0","article-title":"The neurological evaluation scale (NES): A structured instrument for the assessment of neurological signs in schizophrenia","volume":"27","author":"RW Buchanan","year":"1989","journal-title":"Psychiatry Res"},{"key":"pone.0257946.ref044","unstructured":"(No Title). [cited 23 Apr 2021]. Available: https:\/\/www.danskernessundhed.dk\/Spoergeskema.html"},{"key":"pone.0257946.ref045","first-page":"111","article-title":"Consensus guidelines for lumbar puncture in patients with neurological diseases","volume":"8","author":"S Engelborghs","year":"2017","journal-title":"Alzheimer\u2019s Dement Diagnosis, Assess Dis Monit."},{"key":"pone.0257946.ref046","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1038\/s41380-019-0381-9","article-title":"Correction: Cerebrospinal fluid markers of inflammation and infections in schizophrenia and affective disorders: a systematic review and meta-analysis","author":"S Orlovska-Waast","year":"2019","journal-title":"Molecular psychiatry. England"},{"key":"pone.0257946.ref047","first-page":"11","article-title":"IgG Index Revisited: Diagnostic Utility and Prognostic Value in Multiple Sclerosis","author":"Y Zheng","year":"2020","journal-title":"Front Immunol."},{"key":"pone.0257946.ref048","first-page":"6","article-title":"The diagnostic value of IgG index versus oligoclonal bands in cerebrospinal fluid of patients with multiple sclerosis","author":"CS Simonsen","year":"2020","journal-title":"Mult Scler J\u2014Exp Transl Clin."},{"key":"pone.0257946.ref049","first-page":"1","article-title":"Cytokine Alterations in Schizophrenia: An Updated Review","volume":"10","author":"S Momtazmanesh","year":"2019","journal-title":"Article"},{"key":"pone.0257946.ref050","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.schres.2018.12.017","article-title":"Neutrophil-to-lymphocyte ratio in schizophrenia: A systematic review and meta-analysis","author":"V Karageorgiou","year":"2019","journal-title":"Schizophrenia Research. Elsevier B.V."},{"key":"pone.0257946.ref051","doi-asserted-by":"crossref","first-page":"36859","DOI":"10.1136\/bmjopen-2020-036859","article-title":"Neutrophil-lymphocyte ratio across psychiatric diagnoses: a cross-sectional study using electronic health records","volume":"10","author":"A Brinn","year":"2020","journal-title":"BMJ Open"},{"key":"pone.0257946.ref052","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1111\/acps.13140","article-title":"Meta\u2010analysis of total and differential white blood cell counts in schizophrenia","volume":"142","author":"AJ Jackson","year":"2020","journal-title":"Acta Psychiatr Scand"},{"key":"pone.0257946.ref053","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1038\/mp.2015.87","article-title":"C-reactive protein is increased in schizophrenia but is not altered by antipsychotics: Meta-analysis and implications","volume":"21","author":"BS Fernandes","year":"2016","journal-title":"Mol Psychiatry"},{"key":"pone.0257946.ref054","first-page":"1971","volume-title":"Psychological Medicine","author":"E. Bora","year":"2019"},{"key":"pone.0257946.ref055","doi-asserted-by":"crossref","first-page":"1696","DOI":"10.1038\/mp.2016.3","article-title":"A meta-analysis of blood cytokine network alterations in psychiatric patients: Comparisons between schizophrenia, bipolar disorder and depression","author":"DR Goldsmith","year":"2016","journal-title":"Molecular Psychiatry"},{"key":"pone.0257946.ref056","first-page":"122","volume-title":"Neuroscience and Biobehavioral Reviews","author":"E Capuzzi","year":"2017"},{"key":"pone.0257946.ref057","article-title":"Cerebrospinal fluid markers of inflammation and infections in schizophrenia and affective disorders: a systematic review and meta-analysis","author":"S Orlovska-Waast","year":"2019","journal-title":"Mol Psychiatry"},{"volume-title":"R: A language and environment for statistical computing","year":"2018","author":"R Core Team","key":"pone.0257946.ref058"},{"journal-title":"Survival Analysis [R package survival version 3.2\u201310]","year":"2021","author":"TM Therneau","key":"pone.0257946.ref059"},{"key":"pone.0257946.ref060","article-title":"The REDCap consortium: Building an international community of software platform partners","author":"PA Harris","year":"2019","journal-title":"Journal of Biomedical Informatics. Academic Press Inc."},{"key":"pone.0257946.ref061","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/j.jbi.2008.08.010","article-title":"Research electronic data capture (REDCap)-A metadata-driven methodology and workflow process for providing translational research informatics support","volume":"42","author":"PA Harris","year":"2009","journal-title":"J Biomed Inform"},{"journal-title":"The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses","year":"2000","author":"G Wells","key":"pone.0257946.ref062"},{"key":"pone.0257946.ref063","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1007\/978-3-319-01225-4_4","article-title":"Techniques, contraindications, and complications of CSF collection procedures","author":"E Niemantsverdriet","year":"2015","journal-title":"Cerebrospinal Fluid in Clinical Neurology. 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