Portuguese Researchers Study Motivation and the Placebo Effect in Parkinson's Disease Clinical Trial Participation
In a recent column in the San Francisco Chronicle, Michael J. Fox outlined a vision for speeding progress toward breakthrough treatments and cures for disease by increasing the flow of participants into clinical research studies. The Michael J. Fox Foundation (MJFF) has made clinical trial recruitment an imperative, recently launching Fox Trial Finder, a Web tool to connect willing volunteers with the trials that need them.
But what makes someone with Parkinson's decide to participate in clinical trials (or not)? A research group based in Portugal set out to increase understanding of the factors that influence this decision, in the hope that identifying and addressing patients' motivations and concerns around participation could aid recruitment for potential future trials.
Anabela Valadas and colleagues found that their respondents largely focused their concerns on the placebo aspects of trial participation. Their findings also suggest that patients require education on placebo and on what is entailed in participating in a trial that includes a placebo.
Tor Wager, director of the Cognitive and Affective Neuroscience laboratory at the University of Colorado, Boulder, is being funded by MJFF to investigate the placebo effect in PD trials. He talked to MJFF about the recent findings, and his own ongoing work.
MJFF: Please describe what a placebo is and the role it plays in clinical research.
TW: A placebo is a treatment that does not have any actual drug in it, like the proverbial "sugar pill." There are many reasons patients might improve when they participate in a clinical trial: They may be more optimistic, they may respond to the care and attention of the clinical team. Participating in the trial may provide social and physical support that helps people stay better for longer. In this way, participating in a trial with a potentially innovative therapy may be therapeutic in and of itself.
By comparing active treatments to placebo, researchers hope to isolate whether the treatment has any specific beneficial effect. Therefore, placebos are critical for separating the specific effects of new treatments from the other potential benefits of participating in a clinical trial.
MJFF: What is surprising to you about the Portugese team's findings?
TW: I was most surprised that patients said they understood the consent forms for the trials they had participated in, when in fact their answers revealed that they didn't understand that they might be getting a placebo.
This is important because if participants in clinical trials don't realize that they are getting a placebo, they are likely to believe that they are certainly getting a real drug. That belief leads to enhanced positive expectancies, which could improve outcomes for patients taking placebo and drug alike, making it harder to isolate the specific effects of the treatment being studied.
MJFF: Placebo seems to be a very active area of research. A December 2010 study (not in Parkinson's disease) by Ted Kaptchuk at Beth Israel Deaconess Medical Center (Harvard Medical School) showed that a placebo made people feel better even when they were told outright it was a placebo. What can we learn from this?
TW: In a way, the Valadas study sheds some light on the Kaptchuk study. Even if patients are informed that they could receive a placebo treatment, they may not believe they will be the one to receive the placebo. This is what Valadas showed. They likely also believe in the implicit social contract that underlies clinical trials: If I am suffering, and you are studying me to try to help me, then you are going to provide me with the treatment that is the most helpful to me. In a nutshell, the effect Kaptchuk observed could be a result of the ambiguity about placebo (whether you will get one, and whether it will help you anyway) coupled with the caring therapeutic environment of the clinical trial.
Our lab is working with The Michael J. Fox Foundation to understand the effects of positive expectations in Parkinson's disease specifically. We are interested in the consequences of taking the placebo itself -- if participating in a clinical trial improves optimism, energy, and performance, even if one is taking a placebo, then those psychological factors and the brain processes that underlie them are clinically important in their own right.
MJFF: Tell us more about your collaboration with MJFF.
TW: Our project uses functional magnetic resonance imaging (fMRI) to study placebo effects on the functions of the motor and dopamine systems in Parkinson's patients. fMRI is interesting because it can measure the relationship between the brain and behavior in a living human brain.
We are studying how Parkinson's patients' brain activity during motor and dopaminergic reward-learning tasks changes with active medication (this varies by patient but usually involves apomomorphine) and placebo treatments, and this is helping us to learn more about whether placebo treatments affect biological markers of Parkinson's disease.
MJFF: If a placebo can affect biological markers of PD, this would imply that it is more than the psychological phenomenon most people think of — "mind over matter."
TW: That's right. We are aiming to find out whether there might be an actual neurological benefit of placebo, as in, might patients be getting a benefit from placebo similar to the benefit they would get from PD therapies themselves?
MJFF: If this were to be demonstrated, what would the next research steps be?
TW: Establishing which brain systems are affected by placebo in PD will provide insight into whether clinical trials should be designed to enhance or eliminate placebo effects. If placebo treatments affect the same brain systems as active medications like levodopa, then designing a clinical trial to eliminate placebo effects may actually eliminate the effects of the drug as well.
MJFF: Why is that?
TW: To eliminate the placebo effect, individuals who respond to the placebo are sometimes eliminated in an initial "wash-out" phase of the trial. If placebo treatments affect the same brain systems as active medications like levodopa, then removing the placebo responders would be removing the individuals who respond best to the drug as well, leaving in the trial only those who will obtain little benefit from either placebo or active drug.
In fact, there are already at least three small-scale studies that have shown that patients taking placebo show similar reductions in symptoms to those who are taking levodopa. Two of these studies see dopamine release in the striatum with placebo; the third sees changes in subthalamic nucleus firing. These changes are consistent with an actual therapeutic stimulation of the area.
MJFF: What is your takeaway from this?
TW: The best treatment may combine both the optimism of enlisting in clinical trials with an actual drug. Regardless, when people that think they are taking a drug, they seem to do better.
Bret Rutherford and Steven Roose at Columbia University have worked on this very idea in studying depression. They compare double-blind studies with comparator trials, a relatively new type of clinical trial design. In comparator trials half the participants know that they are receiving the experimental drug, while the other half know they are receiving another drug that is already approved to treat patients.
Rutherford and Roose found that patients did better on clinical measures of depression when they were in a comparator trial (100% chance of getting a real drug) than in a double-blind trial (50% chance of receiving the drug), even when comparing subjects who all received the same drug. So in this case, it helped to know you were getting the drug, even among patients who were all taking the same thing.
NOTE: The medical information contained in this article is for general information purposes only. The Michael J. Fox Foundation has a policy of refraining from advocating, endorsing or promoting any drug therapy, course of treatment, or specific company or institution. It is crucial that care and treatment decisions related to Parkinson's disease and any other medical condition be made in consultation with a physician or other qualified medical professional.