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Psychol Med. 2017 Feb;47(3):471-483. doi: 10.1017/S0033291716002658. Epub 2016 Oct 24.

Interplay of hippocampal volume and hypothalamus-pituitary-adrenal axis function as markers of stress vulnerability in men at ultra-high risk for psychosis.

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Department of Psychiatry,Prevention and Early Intervention Program for Psychosis, DouglasMental Health University Institute,McGill University,Montréal,Québec,Canada.
Departments of Neurology & Neurosurgery, and Biomedical Engineering,Brain Imaging Centre,Montreal Neurological Institute,McGill University,Montréal,Québec,Canada.
Departments of Psychiatry, and Psychology,McGill Centre for Studies in Aging,Douglas Mental Health University Institute,McGill University,Montréal,Québec,Canada.



Altered hypothalamus-pituitary-adrenal (HPA) axis function and reduced hippocampal volume (HV) are established correlates of stress vulnerability. We have previously shown an attenuated cortisol awakening response (CAR) and associations with HV specifically in male first-episode psychosis patients. Findings in individuals at ultra-high risk (UHR) for psychosis regarding these neurobiological markers are inconsistent, and assessment of their interplay, accounting for sex differences, could explain incongruent results.


Study participants were 42 antipsychotic-naive UHR subjects (24 men) and 46 healthy community controls (23 men). Saliva samples for the assessment of CAR were collected at 0, 30 and 60 min after awakening. HV was determined from high-resolution structural magnetic resonance imaging scans using a semi-automatic segmentation protocol.


Cortisol measures and HV were not significantly different between UHR subjects and controls in total, but repeated-measures multivariate regression analyses revealed reduced cortisol levels 60 min after awakening and smaller left HV in male UHR individuals. In UHR participants only, smaller left and right HV was significantly correlated with a smaller total CAR (ρ = 0.42, p = 0.036 and ρ = 0.44, p = 0.029, respectively), corresponding to 18% and 19% of shared variance (medium effect size).


Our findings suggest that HV reduction in individuals at UHR for psychosis is specific to men and linked to reduced post-awakening cortisol concentrations. Abnormalities in the neuroendocrine circuitry modulating stress vulnerability specifically in male UHR subjects might explain increased psychosis risk and disadvantageous illness outcomes in men compared to women.


Cortisol; hippocampus; hypothalamus-pituitary-adrenal axis; sex differences; stress; ultra-high risk for psychosis

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