Reduced hippocampal volume and hypothalamus–pituitary–adrenal axis function in first episode psychosis: Evidence for sex differences

•We examined sex differences in neurobiological markers of stress in psychosis.•Hippocampal volume and cortisol levels to awakening are reduced in male patients.•Male first episode psychosis patients show markers of high stress vulnerability.•Neurobiological deficits relate to poor outcome in male but not female patients.•The neural-diathesis stress model of schizophrenia is particularly valid for men.

BackgroundHippocampal volume (HV) decline is an important marker of psychosis and has been associated with hypothalamus–pituitary–adrenal (HPA) axis dysregulation in various disorders. Given recent findings of sex differences in HPA axis function in psychosis, the current study investigated differences in HV in male and female first episode psychosis (FEP) patients and controls and the interaction of HV with the cortisol awakening response (CAR) and symptoms.MethodsFifty-eight patients with a diagnosis of FEP (39 men, 19 women) and 27 healthy community controls (15 men, 12 women) underwent structural magnetic resonance imaging (MRI) on a 1.5 T scanner. Hippocampal volume was determined using previously established segmentation protocols. Saliva samples for cortisol assessment were collected at 0, 30 and 60 min after awakening. Psychotic symptoms were assessed with the Scale for Assessment of Positive Symptoms (SAPS), the Scale for Assessment of Negative Symptoms (SANS) and the Global Assessment of Functioning (GAF) scale.ResultsMale patients had significantly smaller left and right HVs compared to male controls, which appeared to be secondary to global brain volume differences. However, even when controlling for overall brain size, male patients showed smaller HV compared to female patients. The CAR was significantly lower in male patients compared to male controls and female patients. Only in male patients, smaller left HV was significantly associated with a blunted CAR, and smaller HV bilaterally was related to positive psychotic symptoms and lower levels of functioning.ConclusionsWe propose that reduced hippocampal volume and an attenuated cortisol awakening response are related markers of increased stress vulnerability in male psychosis patients and that both contribute to the unfavorable clinical picture in men.