title: C-reactive protein concentrations across the mood spectrum in bipolar disorder: a systematic review and meta-analysis.
abstract: BACKGROUND
  Inflammatory processes and neural-immune interactions have been implicated in the pathogenesis of psychiatric conditions, but studies in bipolar disorder are inconclusive so far. We aimed to investigate whether peripheral concentrations of C-reactive protein (CRP), an acute-phase response protein of inflammatory activity, are increased in bipolar disorder across the mood spectrum.
  
  
  METHODS
  In this systematic review and meta-analysis, we searched MEDLINE, the Cochrane Library, Scopus, and Web of Knowledge from database inception to Aug 14, 2016, for studies that measured serum and plasma CRP concentrations in adult patients with bipolar disorder (as defined by DSM-IV-TR) and healthy controls. We extracted data from published reports. We did three between-group meta-analyses comparing CRP concentrations in patients in mania, depression, or euthymia, with those in healthy controls (cross-sectional studies), and two within-group meta-analyses comparing changes in CRP concentrations before and after treatment of an index manic or depressive episode (longitudinal studies). We used Hedges' adjusted g to calculate effect sizes and pooled results using random-effect models. We also did meta-regression analyses by mood state to investigate possible moderators of CRP concentrations.
  
  
  RESULTS
  We identified 27 studies representing 2161 patients with bipolar disorder and 81 932 healthy controls. Compared with healthy individuals, CRP concentrations were moderately increased in people with bipolar disorder during depression (g 0·67, 95% CI 0·23 to 1·11; p=0·003) and euthymia (0·65, 0·40 to 0·90; p<0·0001) and more substantially increased during mania (0·87, 0·58 to 1·15; p<0·0001). The extent of the increases in CRP concentrations in mania and depression was not related to symptom severity (p=0·256 for mania and p=0·626 for depression). CRP concentrations were moderately decreased after resolution of an index manic episode (-0·36, -0·66 to -0·05; p=0·022) and slightly decreased after resolution of an index depressive episode (-0·18, -0·30 to -0·07; p=0·002).
  
  
  CONCLUSIONS
  CRP concentrations are increased in bipolar disorder regardless of mood state, but are higher during mania than in depression and euthymia, suggesting an increased inflammatory burden in mania.
  
  
  BACKGROUND
  None.
authors.affiliation: IMPACT Strategic Research Centre, Deakin University School of Medicine, and Barwon Health, Geelong, VIC, Australia; Laboratory of Calcium Binding Proteins in the Central Nervous System, Department of Biochemistry, Federal University of Rio Grande do Sul, Porto Alegre, Brazil. Electronic address: brisasf@gmail.com.
authors.forename: Brisa S
authors.initials: BS
authors.lastname: Fernandes
authors.affiliation: Department of Psychiatry, University of Magdeburg, Magdeburg, Germany.
authors.forename: Johann
authors.initials: J
authors.lastname: Steiner
authors.affiliation: Institute of Psychology, Department of Clinical Psychology, Leiden University Medical Center, Leiden, Netherlands; Leiden Institute for Brain and Cognition, Leiden University Medical Center, Leiden, Netherlands.
authors.forename: Marc L
authors.initials: ML
authors.lastname: Molendijk
authors.affiliation: IMPACT Strategic Research Centre, Deakin University School of Medicine, and Barwon Health, Geelong, VIC, Australia.
authors.forename: Seetal
authors.initials: S
authors.lastname: Dodd
authors.affiliation: Laboratory of Calcium Binding Proteins in the Central Nervous System, Department of Biochemistry, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: Patricia
authors.initials: P
authors.lastname: Nardin
authors.affiliation: Laboratory of Calcium Binding Proteins in the Central Nervous System, Department of Biochemistry, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: Carlos-Alberto
authors.initials: CA
authors.lastname: Gonçalves
authors.affiliation: IMPACT Strategic Research Centre, Deakin University School of Medicine, and Barwon Health, Geelong, VIC, Australia.
authors.forename: Felice
authors.initials: F
authors.lastname: Jacka
authors.affiliation: Translational Psychiatry Research Group and Department of Clinical Medicine, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil.
authors.forename: Cristiano A
authors.initials: CA
authors.lastname: Köhler
authors.affiliation: Center for Pattern Recognition and Data Analytics, School of Information Technology, Deakin University, Geelong, VIC, Australia.
authors.forename: Chandan
authors.initials: C
authors.lastname: Karmakar
authors.affiliation: Translational Psychiatry Research Group and Department of Clinical Medicine, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil.
authors.forename: André F
authors.initials: AF
authors.lastname: Carvalho
authors.affiliation: IMPACT Strategic Research Centre, Deakin University School of Medicine, and Barwon Health, Geelong, VIC, Australia; Florey Institute for Neuroscience and Mental Health, Department of Psychiatry and Orygen, The National Centre of Excellence in Youth Mental Health, University of Melbourne, Parkville, VIC, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Berk
mesh_terms: D001714:Bipolar Disorder / Q000097:blood* / Q000523:psychology*; D002097:C-Reactive Protein / Q000378:metabolism*; D006801:Humans; D016032:Randomized Controlled Trials as Topic
chemical_list: D002097:C-Reactive Protein