title: A theoretical framework informing research about the role of stress in the pathophysiology of bipolar disorder.
abstract: BACKGROUND
  The staggering illness burden associated with Bipolar Disorder (BD) invites the need for primary prevention strategies. Before preventative strategies can be considered in individuals during a pre-symptomatic period (i.e., at risk), unraveling the mechanistic steps wherein external stress is transduced and interacts with genetic vulnerability in the early stages of BD will be a critical conceptual necessity.
  
  
  METHODS
  Herein we comprehensively review extant studies reporting on stress and bipolar disorder. The overarching aim is to propose a conceptual framework to inform research about the role of stress in the pathophysiology of BD. Computerized databases i.e. PubMed, PsychInfo, Cochrane Library and Scielo were searched using the following terms: "bipolar disorder" cross-referenced with "stress", "general reaction to stress", "resilience", "resistance", "recovery" "stress-diathesis", "allostasis", and "hormesis".
  
  
  RESULTS
  Data from literature indicate the existence of some theoretical models to understand the influence of stress in the pathophysiology of BD, including classical stress-diathesis model and new models such as allostasis and hormesis. In addition, molecular mechanisms involved in stress adaptation (resistance, resilience and recovery) can also be translated in research strategies to investigate the impact of stress in the pathophysiology of BD.
  
  
  CONCLUSIONS
  Most studies are retrospective and/or cross sectional, do not consider the period of development, assess brain function with only one or few methodologies, and use animal models which are not always similar to human phenotypes.
  
  
  CONCLUSIONS
  The interaction between stress and brain development is dynamic and complex. In this article we proposed a theoretical model for investigation about the role of stress in the pathophysiology of BD, based on the different kinds of stress adaptation response and their putative neurobiological underpinnings.
authors.affiliation: Program for Recognition and Intervention in Individuals in at Risk Mental State, Department of Psychiatry, Universidade Federal de São Paulo, São Paulo, Brazil. elisabrietzke@hotmail.com
authors.forename: Elisa
authors.initials: E
authors.lastname: Brietzke
authors.forename: Rodrigo Barbachan
authors.initials: RB
authors.lastname: Mansur
authors.forename: Joanna
authors.initials: J
authors.lastname: Soczynska
authors.forename: Alissa M
authors.initials: AM
authors.lastname: Powell
authors.forename: Roger S
authors.initials: RS
authors.lastname: McIntyre
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology*; D052636:Allostasis / Q000502:physiology; D000818:Animals; D035843:Biomedical Research / Q000379:methods*; D001714:Bipolar Disorder / Q000150:complications / Q000503:physiopathology* / Q000523:psychology*; D004198:Disease Susceptibility / Q000503:physiopathology; D059165:Hormesis / Q000502:physiology; D006801:Humans; D008954:Models, Biological; D009490:Neurosecretory Systems / Q000503:physiopathology*; D013315:Stress, Psychological / Q000150:complications / Q000503:physiopathology* / Q000523:psychology*