Investigating the Mechanisms of Placebo Anxiolysis

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.

There is a need to develop improved treatments for anxiety disorders. Placebo-controlled trials are presently the gold-standard test of a novel anxiolytic. However, placebo treatment can also cause clinical improvement, which has implications for the design and evaluation of clinical trials. Although the placebo response has been much explored in pain, we know little about placebo anxiolysis. Placebo analgesia involves the endogenous opioid system, and converging evidence suggests this system might also be important in the pathophysiology of psychiatric illness (Bandelow et al., 2010) and anxiety regulation (Colasanti et al., 2011). Previous research funded by the MRC has allowed us to extend and validate an experimental 7.5% carbon dioxide (CO2) inhalational human model of anxiety for treatment development. We will use this model to develop an experimental placebo procedure. Using this placebo procedure, we will carry out a randomised triple-blind study of the opioid antagonist naltrexone to test our hypothesis that endogenous opioids mediate placebo anxiolysis.

We will seek further evidence for the role of endogenous opioids in anxiety regulation through functional neuroimaging. We will ask healthy participants to undergo functional magnetic resonance imaging (fMRI) while they complete an emotional cognitive reappraisal task under two conditions: naltrexone and placebo. This task is known to activate emotional regulatory circuits in the brain. We will correlate the functional connectivity between opioidergic centres (shown by the contrast placebo>naltrexone) with subsequent response to CO2 challenge.

This proposal provides a timely and cost-effective test of the hypothesis that endogenous opioids are important in anxiety regulation. If so, this will provide a step-change in our understanding of placebo anxiolysis. This understanding will inform the design of future clinical trials and allow us to explore novel therapeutic targets for anxiety disorders.

There is a need to develop improved treatments for anxiety, ideally through the use of validated experimental human models of the condition that improve on the poor predictability of preclinical animal models. Placebo-controlled studies are the current 'gold-standard' measure of efficacy of a psychiatric treatment. However, placebo administration can also cause clinical improvement (a placebo response), which can impact the interpretation of trial results. I plan to test whether placebo anxiolysis is mediated by the endogenous opioid system, and to understand the role the endogenous opioid system plays in anxiety regulation through functional neuroimaging. This will identify novel therapeutic targets for anxiolytic treatments, and help us to better design clinical trials.

The following groups will potentially benefit from this research:
1. Patients with anxiety, their families, and their employers. Anxiety disorders are common with an estimated 12-month prevalence of 14% and lifetime prevalence of 17-21% (Wittchen et al., 2011). Generalised anxiety disorder (GAD) is characterised by excessive worry that is difficult to control, irritability, poor concentration, sleep disturbance and an increased risk of co-morbid psychiatric and physical illness. The cost of anxiety disorders in Europe are estimated to be EUR 74.4 billion (Olesen et al., 2011). Our results might highlight a novel function of the endogenous opioid system, suggesting its possible role in the aetiology and pathophysiology of anxiety disorders. In the medium term, this project has potential to identify novel therapeutic targets, and thus directly improve treatment and patient outcomes. Further, there is potential via this model to explore whether placebo effects can be used to enhance current treatments for anxiety. This will improve the lives of patients and their carers. Employers will also see a reduction in lost staff hours due to improved treatments.

2. Patients with other related disorders, their families and employers. Anxiety is a prominent feature seen in a number of chronic health conditions. Anxiety symptoms overlaying physical symptoms can exacerbate chronic conditions. By improving our understanding of anxiety regulation and through development of better treatments, I hope to improve outcomes for these patients. This will also benefit those who care for patients with chronic conditions, and those who employ them.

3. The NHS and its clinicians (psychiatrists, psychologists, physicians, general practitioners, etc.). The 'ideal treatment' for anxiety does not exist. Many patients do not respond to initial psychological or pharmacological treatments. Further, psychological treatments are limited in availability, and medications often cause unwanted side-effects. This research has the potential to improve treatments for anxiety disorders. As a result, NHS resources will be used more efficiently. Clinicians working in the area of affective disorders in primary and secondary medical care settings will be able to better care for their patients. These clinicians will thus have more time to spend helping other patients, benefiting all those who use the health service.

4. Researchers in the field of placebo studies. Through collaboration with other scientists researching the placebo effect, our experimental placebo procedure has the potential to answer many questions and test various hypotheses regarding placebo responses. For example, we can pharmacologically challenge the placebo response to understand which neurotransmitters are involved, as we plan to do. We could also explore whether information given to participants or changes in the setting can alter the placebo response.

5. Pharmaceutical industry. The identification of novel therapeutic targets could lead to novel treatments being developed for anxiety disorders. Increased knowledge of the causes and mechanisms of the placebo response will also lead to improved clinical trial design.