Intranasal Oxytocin: The End of Fear?

Deborah Brauser

November 07, 2014

(Updated Nov. 7, 2014) Intranasal oxytocin (multiple brands) may enhance fear extinction therapy for patients with anxiety disorders, preliminary research suggests.

A randomized controlled trial of 62 healthy male participants showed that those who received intranasal oxytocin soon after undergoing a fear conditioning task had increased inhibition, or a tamping down, of amygdalar responses during extinction therapy compared with matched peers who received placebo. They also showed increased signaling in the medial prefrontal cortex (mPFC).

"[T]he results of our study indicate that a 24 IU single-dose administration of OXT [oxytocin] increases fear extinction–related frontal brain activity and connectivity, and dampens fear and safety-related amygdalar activity along with electrodermal responses," the investigators, led by Monika Eckstein, PhD student from the Department of Psychiatry and the Division of Medical Psychology at the University of Bonn, Germany, write.

The study was published online October 29 in Biological Psychiatry.

Intriguing Hypothesis

It is thought patients with anxiety disorders have decreased amygdala inhibition (hyperaction) during fear responses and deficient encoding in mPFC circuits.

The investigators note that the lack of inhibition in the amygdala and problems with encoding in the mPFC in patients with anxiety disorders after undergoing extinction therapy "often results in a return of fear, thus limiting control over anxiety."

However, they add that the possibility that use of a pharmacologic agent may improve both responses to conditioned fear is an "intriguing hypothesis." For the study, investigators assessed whether the addition of oxytocin would modulate extinction learning.

"Previous studies have already indicated anxiolytic effects of oxytocin, especially a downregulation of the amygdala, a core center of fear in our brain," coinvestigator Rene Hurlemann, MD, PhD, professor in the Department of Psychiatry at the University of Bonn, told Medscape Medical News.

The current study included 62 healthy, left-handed male volunteers (mean age, 24.6 years) who were randomly assigned to receive either a 24 IU intranasal dose of synthetic oxytocin or matching placebo.

They also underwent a "Pavlovian fear conditioning paradigm," which consisted of neutral conditioned stimuli of face and house photos shown sometimes on their own and sometimes paired with brief electric shocks (aversive stimulus).

Participants also underwent functional magnetic resonance imaging (fMRI) scans 30 minutes after treatment.

Results showed that the oxytocin group had increased electrodermal responses and prefrontal cortex signals to conditioned fear during the early phase of extinction therapy and "enhanced decline" of skin conductance responses during the late phase.

The oxytocin group also showed a reduction in amygdala responsiveness during both phases.

Dr Hurlemann reported that this latter finding was expected.

"What was surprising, though, was an increase in prefrontal cortex responses together with a greater decline of skin conductance responses as a consequence of oxytocin treatment," he said.

"Although our results may provide preliminary evidence for a clinical use of [oxytocin], many questions...need to be addressed in future research," the investigators note.

Study limitations cited included the fact that fear acquisition and extinction were performed on the same day instead of being spread out over several days and that it is not known whether the effects of oxytocin can be extrapolated from the type of fear conditioning used here to other types, such as evaluative conditioning.

In addition, because only healthy men were assessed, the findings need to be replicated in women, they note.

Still, the findings provide "important mechanistic insights into beneficial effects of oxytocin in fear extinction, which is thought to be the key learning process underlying cognitive behavioral therapy (exposure) of anxiety disorders," said Dr Hurlemann.

"Exciting" Research

"Overall, I think this is a great study," Dean T. Acheson, PhD, assistant professor in the Department of Psychiatry at the University of California, San Diego, School of Medicine, told Medscape Medical News.

Dr Dean Acheson

"And it supports some findings from our own laboratory suggesting that oxytocin can facilitate aspects of fear extinction learning," he added.

Dr Acheson, who was not involved with this research, published a study last year in Psychopharmacology that examined 44 healthy participants who underwent a conditioned fear acquisition procedure, after which one half were randomly assigned to receive intranasal oxytocin and the other half, placebo. All participants then underwent extinction training 45 minutes after treatment.

Results showed that the participants receiving oxytocin had "increased fear-potentiated startle responding" during the early stage of extinction training and significantly higher recall of fear extinction 24 hours later in comparison with the placebo group.

Dr Acheson noted that use of fMRI in the new study was especially interesting.

"These results not only support the facilitative effect on fear extinction but also suggests a mechanism, which is important moving forward," he said.

However, he pointed out that although "this is a really exciting area," more research is needed.

"I think we need to have some caution at this point. Both of these studies have only involved healthy humans. So we really don't know how this treatment might affect a clinical population," he said.

"This study should certainly stimulate further research into the possibility of this role for oxytocin. But at this point, we really need to get some good data with clinical populations," concluded Dr Acheson.

The study authors and Dr Acheson have reported no relevant financial relationships.

Biol Psychiatry. Published online October 29, 2014. Abstract

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