Oxytocin modulates hippocampal perfusion in people at clinical high risk for psychosis

Cathy Davies,Paul Allen,Silvia Murguia,Gemma Modinos,Marco Cappucciati,Sukhi Shergill,Mathilde Antoniades,Grazia Rutigliano,Umberto Provenzani,Philip Mcguire,Daniel Ståhl ,Steven Williams ,David Taylor,Paul Morrison,Valentina Ramella-Cravaro,Fernando Zelaya,Yannis Paloyelis,Dominic Oliver,Andrea De Micheli,Paolo Fusar‐Poli

doi:10.1038/s41386-018-0311-6

Abstract

Preclinical and human studies suggest that hippocampal dysfunction is a key factor in the onset of psychosis. People at Clinical High Risk for psychosis (CHR-P) present with a clinical syndrome that can include social withdrawal and have a 20–35% risk of developing psychosis in the next 2 years. Recent research shows that resting hippocampal blood flow is altered in CHR-P individuals and predicts adverse clinical outcomes, such as non-remission/transition to frank psychosis. Previous work in healthy males indicates that a single dose of intranasal oxytocin has positive effects on social function and marked effects on resting hippocampal blood flow. The present study examined the effects of intranasal oxytocin on hippocampal blood flow in CHR-P individuals. In a double-blind, placebo-controlled, crossover design, 30 CHR-P males were studied using pseudo-continuous Arterial Spin Labelling on 2 occasions, once after 40IU intranasal oxytocin and once after placebo. The effects of oxytocin on left hippocampal blood flow were examined in a region-of-interest analysis of data acquired at 22–28 and at 30–36 minutes post-intranasal administration. Relative to placebo, administration of oxytocin was associated with increased hippocampal blood flow at both time points (p = .0056; p = .034), although the effect at the second did not survive adjustment for the effect of global blood flow. These data indicate that oxytocin can modulate hippocampal function in CHR-P individuals and therefore merits further investigation as a candidate novel treatment for this group.

Highlights

At present, there is a lack of effective treatments for individuals at Clinical High Risk of Psychosis (CHR-P [1])
As the CHR-P state progresses to the first episode of psychosis, the functional perturbations once localised to Cornu Ammonis 1 (CA1) may spread to extra-hippocampal regions such as the frontal cortex [7, 8], and excitotoxic as well as atrophic processes culminate in hippocampal volume loss—structural changes— beginning in CA1 [15,16,17]
These findings are consistent with evidence that CHR-P individuals show increased resting regional cerebral blood flow in the hippocampus relative to controls [18, 19], and normalisation of left hippocampal rCBF is associated with remission from the CHR-P state [18]

Summary

Introduction

There is a lack of effective treatments for individuals at Clinical High Risk of Psychosis (CHR-P [1]). As the CHR-P state progresses to the first episode of psychosis, the functional perturbations once localised to ( the left) CA1 may spread to extra-hippocampal regions such as the frontal cortex [7, 8], and excitotoxic as well as atrophic processes culminate in hippocampal volume loss—structural changes— beginning in CA1 [15,16,17] These findings are consistent with evidence that CHR-P individuals show increased resting regional cerebral blood flow (rCBF) in the hippocampus relative to controls [18, 19], and normalisation (reduction) of left hippocampal rCBF is associated with remission from the CHR-P state [18]. Hippocampal rCBF in CHR-P individuals has been correlated with cortical GABA levels [20]

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