Psychosocial stress and psychosis. A review of the neurobiological mechanisms and the evidence for gene-stress interaction

Schizophr Bull. 2008 Nov;34(6):1095-105. doi: 10.1093/schbul/sbn101. Epub 2008 Aug 20.


This article presents evidence suggesting that psychosocial stress may increase risk for psychosis, especially in the case of cumulative exposure. A heuristically useful framework to study the underlying mechanisms is the concept of "behavioral sensitization" that stipulates that exposure to psychosocial stress--such as life events, childhood trauma, or discriminatory experiences--may progressively increase the behavioral and biological response to subsequent exposures. The neurobiological substrate of sensitization may involve dysregulation of the hypothalamus-pituitary-adrenal axis, contributing to a hypothesized final common pathway of dopamine sensitization in mesolimbic areas and increased stress-induced striatal dopamine release. It is argued that, in order to reconcile genetic and environmental influences on the development of psychosis, gene-environment interactions may be an important mechanism in explaining between-subject differences in risk following (cumulative) exposure to psychosocial stress. To date, most studies suggestive of gene-stress interaction have used proxy measures for genetic vulnerability such as a family history of psychosis; studies investigating interactions between molecular genetic measures and psychosocial stressors are still relatively scarce. Preliminary evidence suggests that polymorphisms within the catechol-O-methyltransferase and brain-derived neurotrophic factor genes may interact with psychosocial stress in the development of psychosis; however, extensive further investigations are required to confirm this.

Publication types

  • Review

MeSH terms

  • Adult
  • Alleles
  • Animals
  • Brain / physiopathology*
  • Brain-Derived Neurotrophic Factor / genetics
  • Catechol O-Methyltransferase / genetics
  • Child
  • Disease Models, Animal
  • Dopamine / physiology
  • Gene Expression / genetics
  • Genetic Predisposition to Disease / genetics
  • Genetic Predisposition to Disease / psychology
  • Humans
  • Hypothalamo-Hypophyseal System / physiopathology
  • Pituitary-Adrenal System / physiopathology
  • Risk Factors
  • Schizophrenia / genetics*
  • Schizophrenia / physiopathology*
  • Schizophrenic Psychology*
  • Serotonin Plasma Membrane Transport Proteins / genetics
  • Social Environment*
  • Stress, Psychological / complications*
  • Stress, Psychological / physiopathology


  • Brain-Derived Neurotrophic Factor
  • SLC6A4 protein, human
  • Serotonin Plasma Membrane Transport Proteins
  • Catechol O-Methyltransferase
  • Dopamine