title: Peripheral brain-derived neurotrophic factor (BDNF) as a biomarker in bipolar disorder: a meta-analysis of 52 studies.
abstract: BACKGROUND
  The neurotrophic hypothesis postulates that mood disorders such as bipolar disorder (BD) are associated with a lower expression of brain-derived neurotrophic factor (BDNF). However, its role in peripheral blood as a biomarker of disease activity and of stage for BD, transcending pathophysiology, is still disputed. In the last few years an increasing number of clinical studies assessing BDNF in serum and plasma have been published. Therefore, it is now possible to analyse the association between BDNF levels and the severity of affective symptoms in BD as well as the effects of acute drug treatment of mood episodes on BDNF levels.
  
  
  METHODS
  We conducted a systematic review and meta-analysis of all studies on serum and plasma BDNF levels in bipolar disorder.
  
  
  RESULTS
  Through a series of meta-analyses including a total of 52 studies with 6,481 participants, we show that, compared to healthy controls, peripheral BDNF levels are reduced to the same extent in manic (Hedges' g = -0.57, P = 0.010) and depressive (Hedges' g = -0.93, P = 0.001) episodes, while BDNF levels are not significantly altered in euthymia. In meta-regression analyses, BDNF levels additionally negatively correlate with the severity of both manic and depressive symptoms. We found no evidence for a significant impact of illness duration on BDNF levels. In addition, in plasma, but not serum, peripheral BDNF levels increase after the successful treatment of an acute mania episode, but not of a depressive one.
  
  
  CONCLUSIONS
  In summary, our data suggest that peripheral BDNF levels, more clearly in plasma than in serum, is a potential biomarker of disease activity in BD, but not a biomarker of stage. We suggest that peripheral BDNF may, in future, be used as a part of a blood protein composite measure to assess disease activity in BD.
authors.affiliation: Deakin University, IMPACT Strategic Research Centre, School of Medicine, Geelong, Australia. brisasf@gmail.com.|Laboratory of Calcium Binding Proteins in the Central Nervous System, Department of Biochemistry, Federal University of Rio Grande do Sul, Porto Alegre, Brazil. brisasf@gmail.com.
authors.forename: Brisa S
authors.initials: BS
authors.lastname: Fernandes
authors.affiliation: Institute of Psychology, Department of Clinical Psychology, Leiden University, Leiden, The Netherlands.|Leiden Institute for Brain and Cognition, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Marc L
authors.initials: ML
authors.lastname: Molendijk
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 of Excellence on Mood Disorders, Department of Psychiatry and Behavioral Sciences, Texas Health and Science University, Houston, TX, USA.
authors.forename: Jair C
authors.initials: JC
authors.lastname: Soares
authors.affiliation: Translational Psychiatry Research Group and Department of Clinical Medicine, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil.
authors.forename: Cláudio Manuel G S
authors.initials: CM
authors.lastname: Leite
authors.affiliation: Laboratory of Neuroscience, LIM-27, Institute and Department of Psychiatry, University of Sao Paulo, Sao Paulo, Brazil.|Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of Sao Paulo, Sao Paulo, Brazil.|Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, NIH, Bethesda, MD, USA.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Machado-Vieira
authors.affiliation: Translational Psychiatry Research Group and Department of Clinical Medicine, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil.
authors.forename: Thamara L
authors.initials: TL
authors.lastname: Ribeiro
authors.affiliation: Translational Psychiatry Research Group and Department of Clinical Medicine, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil.
authors.forename: Jéssica C
authors.initials: JC
authors.lastname: Silva
authors.affiliation: Translational Psychiatry Research Group and Department of Clinical Medicine, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil.
authors.forename: Paulo M G
authors.initials: PM
authors.lastname: Sales
authors.affiliation: Center of Excellence on Mood Disorders, Department of Psychiatry and Behavioral Sciences, Texas Health and Science University, Houston, TX, USA.|Center for Translational Psychiatry, Department of Psychiatry and Behavioral Sciences, The University of Texas Medical School at Houston, Houston, TX, USA.|Neuroscience Graduate Program, Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA.|Laboratory of Neurosciences, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciúma, SC, Brazil.
authors.forename: João
authors.initials: J
authors.lastname: Quevedo
authors.affiliation: Laboratory for Neuroimaging, Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, Goethe University, Frankfurt/Main, Germany.
authors.forename: Viola
authors.initials: V
authors.lastname: Oertel-Knöchel
authors.affiliation: Bipolar Disorders Unit, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain.
authors.forename: Eduard
authors.initials: E
authors.lastname: Vieta
authors.affiliation: University of the Basque Country, Biomedical Research Center in Mental Health Net (CIBERSAM), Department of Neurosciences, University of the Basque Country, Leioa, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: González-Pinto
authors.affiliation: Deakin University, IMPACT Strategic Research Centre, School of Medicine, Geelong, Australia.|Florey Institute of Neuroscience and Mental Health, Orygen, The National Centre of Excellence in Youth Mental Health and Orygen Youth Health Research Centre, Parkville, VIC, Australia.|Department of Psychiatry, University of Melbourne, Parkville, VIC, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Berk
authors.affiliation: Translational Psychiatry Research Group and Department of Clinical Medicine, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil. andrefc7@terra.com.br.
authors.forename: André F
authors.initials: AF
authors.lastname: Carvalho
mesh_terms: D015415:Biomarkers / Q000097:blood*; D001714:Bipolar Disorder / Q000097:blood* / Q000188:drug therapy; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism*; D003863:Depression; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged
chemical_list: D015415:Biomarkers; D019208:Brain-Derived Neurotrophic Factor; C579455:BDNF protein, human