Reduced hippocampal size and increased stress sensitivity are associated with psychotic disorder and familial risk for psychosis. However, to what degree the hippocampus is implicated in daily life stress reactivity has not yet been examined. The current study investigated (i) whether familial risk (the contrast between controls, patients and siblings of patients) moderated the relationship between hippocampal volume (HV) and emotional daily stress reactivity and (ii) whether familial risk (the contrast between controls and siblings of patients) moderated the relationship between HV and cortisol daily stress reactivity.

T1-weighted magnetic resonance imaging (MRI) scans were acquired from 20 patients with schizophrenia, 37 healthy siblings with familial risk for schizophrenia and 32 controls. Freesurfer 5.0.0 was used to measure HV. The experience sampling method (ESM), a structured momentary assessment technique, was used to assess emotional stress reactivity, that is the effect of momentary stress on momentary negative affect (NA). In addition, in the control and sibling groups, cortisol stress reactivity was assessed using momentary cortisol levels extracted from saliva.

Multilevel linear regression analyses revealed a significant three-way interaction between group, HV and momentary stress in both the model of NA and the model of cortisol. Increased emotional stress reactivity was associated with smaller left HV in patients and larger total HV in controls. In line with the results in patients, siblings with small HV demonstrated increased emotional and cortisol stress reactivity compared to those with large HV.

HV may index risk and possibly disease-related mechanisms underlying daily life stress reactivity in psychotic disorder.

Hypothalamic–pituitary–adrenal (HPA) axis hyperactivity, associated with increased pituitary volume, may mediate observed alterations in stress reactivity in patients with psychotic disorder. We examined the association between pituitary volume, real-life stress reactivity and genetic liability for psychotic disorder.

Pituitary volumes were derived from magnetic resonance imaging (MRI) scans of 20 patients with psychotic disorder, 37 non-psychotic siblings of these patients, and 32 controls. The Experience Sampling Method (ESM) was used to measure emotional stress reactivity [changes in negative affect (NA) associated with daily life stress] in the three groups, and biological stress reactivity (changes in cortisol associated with daily life stress) in siblings and controls. Interactions between group, stress and pituitary volume in models of NA and cortisol were examined.

Groups did not differ in pituitary volume. Patients showed significantly higher emotional stress reactivity than siblings and controls. In addition, emotional stress reactivity increased with increasing pituitary volume to a greater degree in patients than in controls and siblings. Siblings had higher cortisol levels than controls but did not show increased cortisol reactivity to stress. There was no interaction between pituitary volume, stress and group in the model of cortisol.

Higher pituitary volume was associated with increased emotional stress reactivity in patients with psychotic disorder, siblings and controls. The association was significantly stronger in the patient group, suggesting a process of progressive sensitization mediating clinical outcome.