Stress abnormalities in individuals at risk for psychosis: A review of studies in subjects with familial risk or with “at risk” mental state

Increased sensitivity to stress is known to play an important role in the transition to first episode psychosis (FEP). Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, and, in general, an increased sensitivity to stress, have been hypothesised to be components of the vulnerability to psychosis, but whether these abnormalities are already present before the onset of psychosis has not yet been systematically reviewed. Here we have reviewed all studies examining psychological and biological markers of the stress response in the relatives of psychotic patients and in individuals at Ultra High Risk (UHR) for psychosis. In relatives, there is evidence of increased sensitivity to stress, as shown by increased emotional reactivity to daily life stress, increased adrenocorticotropic hormone (ACTH) in response to stress, increased pituitary volume and reduced hippocampal volume. However, evidence of increased cortisol levels is less consistent. On the other hand, subjects who experience attenuated psychotic symptoms show increased cortisol levels as well as increased pituitary and reduced hippocampal volumes. Moreover, this HPA axis hyperactivity seems to be even greater among those individuals who subsequently develop frank psychosis. In summary, an enhanced HPA axis response to stress appears to be part of the biological vulnerability to psychosis which is present prior to the onset of psychosis. A further increase in cortisol levels during the transition to FEP suggests the presence of an additive factor, possibly environmental, at this stage of the illness. Possible causes and consequences of HPA axis impairment in risk for psychosis are discussed.