In late 2011, many in the mental health community were shocked by a clinical study that suggested neither talk therapy or antidepressant drugs were more effective than a placebo in treating urban patients with major depressive disorder (MDD). The trial, led by Adelphi University’s Jacques Barber and published in the Journal of Clinical Psychiatry, made headlines, with many focusing on what scientists saw as a lack of efficacy in currently available antidepressant medications. But other neuroscientists have argued that the real story behind these findings involves the power of placebo. Those scientists have argued that placebo effects are not imaginary or null treatments as once believed. Rather, the placebo effect is a real phenomenon that results in measureable neurobiological consequences. Understanding what makes a particular person susceptible to placebo, and how that affects the way the brain responds to pain or disease, may change the way clinical drug trials and, perhaps, clinical treatments are administered.
Not a null treatment
Currently, when pharmaceutical companies test new drugs, their scientists compare the drug in question to some sort of placebo. Half the trial participants receive the new medication, the other half are given some kind of substitute such as a sugar pill or a saline injection. Neither the trial participants, nor the clinicians monitoring their progress, know who is getting which. Generally, if the drug results in significantly better clinical outcomes than the placebo, it’s assumed to be effective. Yet Jon-Kar Zubieta, a psychiatrist at the University of Michigan, says you cannot assume that the placebo is a null condition. Using molecular imaging, he and his colleagues have demonstrated that, during pain, the mere expectation of relief can activate internal healing mechanisms in the brain.
“We’ve shown that giving the patient something that they think will relieve pain, even when it is just a saline shot, activates chemical systems like the opioid system and releases endorphins,” he says. “You can look and actually observe the release of these opioids when the placebo is given and see the endogenous analgesic mechanisms working.”
But not everyone responds to placebo in the same way. And given that personality measures have been positively correlated with treatment responses in some neuropsychiatric and substance abuse disorders, Zubieta wondered if perhaps they might also help identify who might respond strongest to placebos as well.
Personality and placebo
To test the idea, Zubieta and his colleagues put healthy people, who had previously filled out a variety of personality trait tests, through a pain challenge, measuring their molecular response via a positron emission tomography (PET) scanner. The researchers placed needles into the masseter muscles of each participant and then infused saline directly into the muscle, leading to an uncomfortable yet not overwhelming sensation of pain. During the placebo condition, the participants were told they would receive relief for their pain—but instead they received a simple saline injection placebo. The PET scans looked specifically at µ-opioid neurotransmission in the brain. The researchers found that participants who scored high in personality traits like resiliency, altruism, and straightforwardness showed greater µ-opioid transmission in areas of the brain like the anterior cingulated cortex, orbitofrontal cortex, and nucleus accumbens. They also reported feeling more pain relief.
“The personality traits that we saw correlated with the placebo induced pain relief were the kind of characteristics that make people more likely to follow instructions, to be open to new experiences, to be more compliant, and to adapt to the environment,” says Zubieta. “So this makes sense. It’s possible that these kind of personality characteristics make these people better patients and better able to interact with the treatment environment and that helps them to turn on these endogenous healing processes.”
More than one 'placebo effect'
Zubieta thinks that future clinical trials should consider placebo as a factor: By knowing who is most susceptible to placebo, clinicians could collect data that would better clarify the true effects of the drugs being tested. Barber, the lead author of the depression trial, isn’t so sure. He worries that it will make clinical trials too complicated.
“You have to remember the reason we do these studies is to try to find treatments for that 'patient in the street,'” he says. “If you add these kinds of variables, it’s hard to know what you will learn from the study. It will make things very complicated and may actually hurt our ability to find new treatments.”
But Damian Finniss, a researcher who studies the placebo effect at the Sydney Medical School, says that while studying placebo is tricky, it is definitely worthwhile. Yet he cautions that it is very complex because there is not a single placebo effect.
“If you were to gather ten different people from any walk of life, on some occasions some will be placebo responders and on other occasions those same people won’t be responders,” he says. “For example, we know that Europeans respond better to tablet placebo where people in the U.S. prefer injectables. We need to understand that past treatment experience, expectations, cultural differences, and the doctor-patient interaction all play a role in the placebo response. It’s a very complex topic and it’s important to realize that there are probably multiple placebo effects in just one clinical interaction.”
He says that understanding that the placebo effect is a valid, biological response, however, is very important, not just in drug trials, but in everyday healthcare interactions. “It’s an exciting time to learn more about placebo effects, to understand which patients are going to better respond to different types of manipulation, and see how that might change the way healthcare is delivered,” he says. “By understanding the placebo response, we can try to use that response with every therapy, in every patient, so we can give them the best help.”