title: The HPA axis in bipolar disorder: Systematic review and meta-analysis.
abstract: OBJECTIVE
  To provide a quantitative and qualitative synthesis of the available evidence on the role of Hypothalamic-Pituitary-Adrenal (HPA) axis in the pathophysiology of Bipolar Disorder (BD).
  
  
  METHODS
  Meta-analysis and meta-regression of case-control studies examining the levels of cortisol, ACTH, CRH levels. Systematic review of stress reactivity, genetic, molecular and neuroimaging studies related to HPA axis activity in BD.
  
  
  RESULTS
  Forty-one studies were included in the meta-analyses. BD was associated with significantly increased levels of cortisol (basal and post-dexamethasone) and ACTH, but not of CRH. In the meta-regression, case-control differences in cortisol levels were positively associated with the manic phase (p=0.005) and participants' age (p=0.08), and negatively with antipsychotics use (p=0.001). Reviewed studies suggest that BD is associated with abnormalities of stress-related molecular pathways in several brain areas. Variants of HPA axis-related genes seem not associated with a direct risk of developing BD, but with different clinical presentations. Also, studies on unaffected relatives suggest that HPA axis dysregulation is not an endophenotype of BD, but seems related to environmental risk factors, such as childhood trauma. Progressive HPA axis dysfunction is a putative mechanism that might underlie the clinical and cognitive deterioration of patients with BD.
  
  
  CONCLUSIONS
  BD is associated with dysfunction of HPA axis activity, with important pathophysiological implications. Targeting HPA axis dysfunctions might be a novel strategy to improve the outcomes of BD.
authors.affiliation: Section of Psychiatry, Department of Neuroscience, Ophthalmology, Genetics and Infant-Maternal Science, University of Genoa, Italy; Institute of Psychiatry, Psychology and Neuroscience, Department of Psychological Medicine, King's College London, London, UK. Electronic address: martino.belvederi@gmail.com.
authors.forename: Martino
authors.initials: M
authors.lastname: Belvederi Murri
authors.affiliation: Section of Psychiatry, Department of Neuroscience, Ophthalmology, Genetics and Infant-Maternal Science, University of Genoa, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Prestia
authors.affiliation: Institute of Psychiatry, Psychology and Neuroscience, Department of Psychological Medicine, King's College London, London, UK.
authors.forename: Valeria
authors.initials: V
authors.lastname: Mondelli
authors.affiliation: Institute of Psychiatry, Psychology and Neuroscience, Department of Psychological Medicine, King's College London, London, UK.
authors.forename: Carmine
authors.initials: C
authors.lastname: Pariante
authors.affiliation: Section of Psychiatry, Department of Neuroscience, Ophthalmology, Genetics and Infant-Maternal Science, University of Genoa, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Patti
authors.affiliation: Section of Psychiatry, Department of Neuroscience, Ophthalmology, Genetics and Infant-Maternal Science, University of Genoa, Italy.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Olivieri
authors.affiliation: Section of Psychiatry, Department of Neuroscience, Ophthalmology, Genetics and Infant-Maternal Science, University of Genoa, Italy.
authors.forename: Costanza
authors.initials: C
authors.lastname: Arzani
authors.affiliation: Section of Psychiatry, Department of Neuroscience, Ophthalmology, Genetics and Infant-Maternal Science, University of Genoa, Italy.
authors.forename: Mattia
authors.initials: M
authors.lastname: Masotti
authors.affiliation: Section of Psychiatry, Department of Neuroscience, Ophthalmology, Genetics and Infant-Maternal Science, University of Genoa, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Respino
authors.affiliation: Section of Psychiatry, Department of Neuroscience and Infant-Maternal Science, University of Sassari, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Antonioli
authors.affiliation: Section of Psychiatry, Department of Neuroscience, Ophthalmology, Genetics and Infant-Maternal Science, University of Genoa, Italy.
authors.forename: Linda
authors.initials: L
authors.lastname: Vassallo
authors.affiliation: Section of Psychiatry, Department of Neuroscience, Ophthalmology, Genetics and Infant-Maternal Science, University of Genoa, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Serafini
authors.affiliation: San Benedetto Hospital, Hermanas Hospitalarias, Department of Clinical Neuroscience, Albese con Cassano, Como, Italy.
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Perna
authors.affiliation: Suicide Prevention Center, Department of Neurosciences, Mental Health and Sensory Organs, Suicide Prevention Center, Sant'Andrea Hospital, Sapienza University of Rome, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pompili
authors.affiliation: Section of Psychiatry, Department of Neuroscience, Ophthalmology, Genetics and Infant-Maternal Science, University of Genoa, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Amore
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D001714:Bipolar Disorder / Q000378:metabolism / Q000503:physiopathology*; D016022:Case-Control Studies; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism / Q000503:physiopathology*; D010913:Pituitary-Adrenal System / Q000378:metabolism / Q000503:physiopathology*
chemical_list: D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D006854:Hydrocortisone
keywords: Bipolar disorder; Cortisol; Depression; Glucocorticoid receptor; HPA Axis; Mania