Anxiolytic Effects of Chronic Intranasal Oxytocin on Neural Responses to Threat Are Dose-Frequency Dependent

<b><i>Introduction:</i></b> Anxiety disorders are prevalent mental 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 human studies have exclusively focused on single-dose (acute) intranasal OT effects. <b><i>Objective:</i></b> To facilitate the translation of the potential anxiolytic mechanism of OT into clinical application, we determined whether the anxiolytic effects of OT are maintained with repeated (chronic) administration or are influenced by dose frequency and trait anxiety. <b><i>Methods:</i></b> In a pre-registered double-blind randomized placebo-controlled pharmaco-fMRI trial the 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 were assessed in <i>n</i> = 147 individuals with high versus low trait anxiety (ClinicalTrials.gov ID: NCT03085654). <b><i>Results:</i></b> OT produced valence, dose frequency, and trait anxiety-specific effects, such that the low-frequency (intermittent) chronic dosage specifically attenuated a neural reactivity increase in amygdala-insula-prefrontal circuits observed in the high anxious placebo-treated subjects in response to threatening but not positive stimuli. <b><i>Conclusions:</i></b> The present trial provides the first evidence that low-dose frequency chronic intranasal OT has the potential to alleviate exaggerated neural threat reactivity in subjects with elevated anxiety levels, suggesting a treatment potential for anxiety disorders.