Today, Rhonda and I interview one of our heroes, Dr. Irving Kirsch, who is a giant in depression research and a fun, down-to-earth human being at the same time! Dr. Kirsch is Associate Director of the Program in Placebo Studies and the Therapeutic Relationship, and a lecturer on medicine at the Harvard Medical School (Beth Israel Deaconess Medical Center). He is also Emeritus Professor of Psychology at the University of Hull (UK) and the University of Connecticut (USA). Dr. Kirsch has published 10 books, more than 250 scientific journal articles and 40 book chapters on placebo effects, antidepressant medication, hypnosis, and suggestion. He originated the concept of response expectancy. This is the expectation that people have that a given treatment or intervention will be helpful. Kirsch’s 2002 meta-analysis on the efficacy of antidepressants influenced official guidelines for the treatment of depression in the United Kingdom. His 2008 meta-analysis was covered extensively in the international media and listed by the British Psychological Society as one of the “10 most controversial psychology studies ever published.” His book, The Emperor’s New Drugs: Exploding the Antidepressant Myth, has been published in English, French, Italian, Japanese, Turkish, and Polish, and was shortlisted for the prestigious “Mind Book of the Year” award. It was also the topic of a 60 Minutes segment on CBS and a 5-page cover story in Newsweek. In 2015, the University of Basel (Switzerland) awarded Irving Kirsch an Honorary Doctorate in Psychology. In 2019, the Society for Clinical and Experimental Hypnosis honored him with their “Living Human Treasure Award.” In today’s podcast, we cover a wide range of topics, including a patient-level reanalysis of all of the data on the effects of antidepressant medications versus placebos submitted to the FDA. This analysis included more than 70,000 depressed individuals and indicated something troubling and surprising. The difference in improvement between individuals treated with antidepressants and individuals receiving antidepressant medications was only 1.8 points on the Hamilton Rating Scale for Depression. This test can range from 0 to 50, and a difference of 1.8 points is not clinically significant. In addition, the beneficial antidepressant effects observed in both the placebo and “antidepressant” groups are large, with reductions of around 10 points or so on the Hamilton Scale. These were the shocking discoveries that led to his popular book, The Emperor’s New Drugs (LINK), and to his appearance on the Sunday evening 60 Minutes TV show. In addition, Dr. Kirsch agreed that tiny difference between the “effects” of antidepressants vs placebos could be the result of problems in the experimental design used by drug companies. Because they give patients in the placebo groups pills with inactive ingredients, there are no side effects in the placebo groups. This makes it fairly easy for individuals to guess what group they were assigned to—the “real” antidepressant group or the placebo group. This might account for the differences in the groups, since many individuals in the medication groups may think, “Hey, I’m getting some side effects. I must be in the antidepressant group. That’s terrific!” This thought would be expected to trigger some mood elevation, but it’s the thought, and not the pill, that causes this. In contrast, some individual in the placebo groups may have the thought, “Hey, I’m not getting any of the side effects they described. I must be in the placebo group!” And this thought may trigger disappointment, and a worsening of depression. This would contribute to differences between the drug and placebo groups in drug company outcome studies with new chemicals that they hope to get approved as “antidepressants.” This problem could easily be corrected by the use of active placebos, like atropine, which produces dry mouth, a side effect of many antidepressants and has been used as an active placebo in a small number of trials. Most of the studies using active placebos have failed to show any significant effect of the antidepressant over the active placebo. Drug companies have been reluctant to implement this change in their research designs, perhaps due to the fear that it will “erase” the tiny differences that they have been reporting. This would be of potential concern since billions of dollars are at stake if the FDA gives you permission to call your new chemical an “antidepressant.” We also discussed Dr. Kirsch’s unlikely journey to Harvard. When he was in England, planning to return to the United States, he asked a colleague at Harvard if it would be possible for him to get a library card so he’d have access to articles in research journals. His colleague told him that it was difficult to obtain a library card for people not affiliated with Harvard. However, they were willing to offer him a position as Instructor on Medicine, given that he was the Associate Director of the Program in Placebo Studies and the Therapeutic Relationship, which was hosted at one of the Harvard teaching hospitals. That’s a wow! But certainly deserved, and a most fortunate affiliation with unanticipated and highly positive consequences that have led to many important discoveries on how the placebo effect actually works. The placebo effect is not a bad thing, and has been one of the doctor’s best “medicines” for hundreds if not thousands of years. On the podcast, we also discussed the confusion—for patients, doctors, and researchers alike—caused by the placebo effect. For example, many people who receive antidepressants do improve, and some recover completely. They will SWEAR by antidepressants, and may feel hurt or disappointed by the results of Dr. Kirsch’s research. But in fact, there is no discernable difference between the effects of placebos and so-called “real” effects. And one of the downsides of the confusion about placebos is that people who take antidepressants and improve have improved because of changes in their thinking, and not from the antidepressant. But they wrongly give credit to the pills they took, whereas they deserve the real credit for overcoming their feelings of depression. We discussed many other topics, including pushback he has received from the psychiatric community and some in the general public as well who have not taken kindly to his findings. I, too, have experienced that when I have summarized the data in the Food and Drug Administration, and have had to be very careful in how I present this information, because none of us want to discourage anyone who is depressed. We have also invited Dr. Kirsch to consult with us on the research design we use in our beta testing of the Feeling Good App, and have developed tests of “expectations” (the so-called placebo effect) that we will use in our latest beta test as well. We want to “walk the walk” and not just “talk the talk” and find out how much the improvement we see in beta testers might be due to a placebo, or “mega-placebo” effect. Rhonda and I were honored and thrilled to have this chance to interview Dr. Irving Kirsch, a friend and research giant for sure! Thanks so much for listening to today’s podcast! Irving, Rhonda, and David