Huneke (Baldwin) - MRC CRTF - Investigating the mechanisms of placebo anxiolysis - Jan 19

Anxiety symptoms are common, and people with anxiety disorders typically have persistent symptoms that cause significant distress, impair everyday function and reduce quality of life. There is a need for improved treatments for patients with anxiety disorders, as many patients do not respond to psychological or pharmacological treatments, and drug treatments can cause unwanted side-effects. We normally test a new treatment by comparing it with a placebo; a 'dummy' treatment with no active ingredients. Sometimes, patients improve when given a placebo, and this is called a 'placebo response'. If many patients show this response in a clinical trial, it can be difficult to establish whether a new treatment works. Learning more about what causes a placebo response should help us to test potential new treatments more reliably. We might also find a previously unknown path to creating new treatments. Placebos have been shown to reduce pain effectively. When many people are given a placebo for pain, chemicals called opioids are released. We do not know if opioids are also released if we give people a placebo for anxiety. We aim to learn about the placebo response in anxiety and to test whether opioids are involved. Objective 1: First, we want to test whether a placebo can reduce a person's anxiety. We plan to test this by giving healthy volunteers a placebo while they breathe air 'enriched' with 7.5% of carbon dioxide (CO2), which is known as 'CO2 challenge'. CO2 challenge is known to increase levels of anxiety. We plan to measure the volunteers' anxiety levels, blood pressure, and heart rate to see whether the placebo makes them less anxious. Objective 2: We want to test whether opioids are released during a placebo response in the CO2 challenge. We will ask another group of healthy volunteers to go through the placebo procedure described above in a new experiment, but will also give them a medication that blocks opioids called naltrexone. If opioids are important in relieving anxiety during a placebo response, then we think participants given naltrexone will remain anxious when inhaling the carbon dioxide. Objective 3: Finally, we want to understand whether opioids are involved in controlling anxiety even without a placebo. To do this, we will carry out a third experiment. We plan to scan healthy volunteers using magnetic resonance imaging (MRI). During the scans our participants will be shown unpleasant images and asked to reinterpret these so that they are less distressing. This task is known to activate brain regions important in controlling emotion. Our participants will then complete the CO2 challenge within 7 days. We want to see whether there is a relationship between activity in brain networks known to release opioids and the level of anxiety caused by CO2 challenge. These experiments will help us to understand the role of opioids in controlling anxiety. This might help us to identify new opportunities for treatment development.