Anxiolytic effects of chronic intranasal oxytocin on neural responses to threat are dose-frequency dependent

Anxiety disorders are prevalent psychiatric conditions characterized by exaggerated anxious arousal and threat reactivity. Animal and human studies suggest an anxiolytic potential of the neuropeptide oxytocin (OT), yet, while a clinical application will require chronic administration protocols previous studies in humans have exclusively focused on single-dose (acute) intranasal OT effects. We aimed at determining whether the anxiolytic effects of OT are maintained with repeated (chronic) administration or are influenced by dose frequency and trait anxiety. A double-blind randomized, placebo-controlled pharmaco-fMRI trial (n=147) determined acute (single-dose) as well as chronic effects of two different dose frequencies of OT (OT administered daily for 5 days or every other day) on emotional reactivity in healthy subjects with high versus low trait anxiety. OT produced valence, dose frequency and trait anxiety specific effects, such that the low-frequency (intermittand) chronic dosage specifically attenuated neural reactivity in amygdala-insula-prefrontal regions in high anxious subjects in response to threatening but not positive stimuli. The present trial provides evidence that low dose frequency chronic oxytocin nasal spray has the potential to alleviate exaggerated neural threat reactivity in subjects with elevated anxiety levels underscoring a treatment potential for anxiety disorders.