title: The effect of mood-stabilizing drugs on cytokine levels in bipolar disorder: A systematic review.
abstract: Cytokine level alterations suggest a role for the immune system in the pathophysiology of bipolar disorder (BD). Pharmacotherapy is an important confounding factor in clinical research on cytokine levels. In this systematic review we collate the evidence on blood cytokine levels in medication-free BD and the effects of single mood-stabilizing drugs on these levels.
  
  
  
  A systematic review was conducted according to the PRISMA statement. We searched the Pubmed and Embase databases for clinical studies reporting either on cytokine levels in medication-free BD or on the effects of single mood-stabilizing drugs on cytokine levels in BD.
  
  
  
  Of the 564 articles screened, 17 were included. Fourteen articles report on medication-free patients with BD and indicate state-related cytokine alterations. Six articles discuss the effect of lithium. Whereas no data on short-term effects of lithium were found, ≥2 months lithium use in euthymic populations is associated with normal cytokine levels. Two studies report no effect of valproate and no studies were found on carbamazepine, lamotrigine or antipsychotics.
  
  
  
  The available studies are characterized by a broad methodological heterogeneity and limited replication between studies.
  
  
  
  This systematic review suggests the presence of state-related cytokine level alterations in medication-free BD with most evidence pointing to a proinflammatory cytokine response in mania. Euthymia and long-term lithium use are associated with normal cytokine levels. To improve our understanding of the impact of mood-stabilizing drugs on cytokine levels, longitudinal studies with medication-free baseline, randomized controlled single-drug treatment protocols and close mood state monitoring are needed.
authors.affiliation: Collaborative Antwerp Psychiatric Research Institute (CAPRI), Department of Biomedical Sciences, University of Antwerp, Belgium; University Psychiatric Hospital Duffel, VZW Emmaüs, Duffel, Belgium. Electronic address: seline.vandenameele@uantwerpen.be.
authors.forename: Seline
authors.initials: S
authors.lastname: van den Ameele
authors.affiliation: Collaborative Antwerp Psychiatric Research Institute (CAPRI), Department of Biomedical Sciences, University of Antwerp, Belgium; University Psychiatric Hospital Duffel, VZW Emmaüs, Duffel, Belgium.
authors.forename: Linda
authors.initials: L
authors.lastname: van Diermen
authors.affiliation: Diabetes Research Center, Vrije Universiteit Brussel, Belgium; Department of Pediatrics, Division of Pediatric Endocrinology, Ghent University Hospital, Ghent, Belgium; Department of Pediatrics and Genetics, Ghent University, Ghent, Belgium.
authors.forename: Willem
authors.initials: W
authors.lastname: Staels
authors.affiliation: Collaborative Antwerp Psychiatric Research Institute (CAPRI), Department of Biomedical Sciences, University of Antwerp, Belgium; University Psychiatric Hospital Duffel, VZW Emmaüs, Duffel, Belgium.
authors.forename: Violette
authors.initials: V
authors.lastname: Coppens
authors.affiliation: Department of Pharmacy, Academic Medical Center, University of Amsterdam, The Netherlands.
authors.forename: Glenn
authors.initials: G
authors.lastname: Dumont
authors.affiliation: Collaborative Antwerp Psychiatric Research Institute (CAPRI), Department of Biomedical Sciences, University of Antwerp, Belgium; University Psychiatric Hospital Duffel, VZW Emmaüs, Duffel, Belgium.
authors.forename: Bernard
authors.initials: B
authors.lastname: Sabbe
authors.affiliation: Collaborative Antwerp Psychiatric Research Institute (CAPRI), Department of Biomedical Sciences, University of Antwerp, Belgium; Psychiatric Hospital Broeders Alexianen, Boechout, Belgium.
authors.forename: Manuel
authors.initials: M
authors.lastname: Morrens
mesh_terms: D000339:Affect / Q000187:drug effects*; D018692:Antimanic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D014150:Antipsychotic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001714:Bipolar Disorder / Q000097:blood* / Q000188:drug therapy*; D016207:Cytokines / Q000097:blood*; D005260:Female; D006801:Humans; D000077213:Lamotrigine; D008094:Lithium / Q000494:pharmacology / Q000627:therapeutic use; D014227:Triazines / Q000494:pharmacology / Q000627:therapeutic use; D014635:Valproic Acid / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D018692:Antimanic Agents; D014150:Antipsychotic Agents; D016207:Cytokines; D014227:Triazines; D014635:Valproic Acid; D008094:Lithium; D000077213:Lamotrigine
keywords: Bipolar disorder; Cytokines; Inflammation; Lithium; Mood-stabilizing drugs; Systematic review