The effects of HPA axis function on cognition and its implications for the pathophysiology of bipolar disorder.

Bipolar disorders (BDs) are common and complex diseases. Recent findings have provided the basis for an integrated approach linking seemingly disparate findings, based on a greater understanding of the effects of stress on those vulnerable to these illnesses and the brain's consequent responses. Genes are associated with this disorder, although their integration into current pathophysiological models is unclear. Manic states are associated with enhanced dopaminergic transmission, and experimental stress enhances dopamine neurotransmission and impairs cognition. Stress activates the hypothalamic-pituitary-adrenal axis, and dysfunction of this axis and impairments in neurocognitive function have both been demonstrated in BD. Glucocorticoid receptors are abnormal in postmortem brain studies in BD and play an important role in the HPA axis. The glucocorticoid receptor antagonist RU-486 has been shown to improve aspects of cognitive function in BD. The implications of these findings for models of pathophysiology are discussed. Future efforts should focus on further integrating the current and emerging research findings into a coherent pathophysiological model that generates testable hypotheses.