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Modern psychiatric drugs are expensive and produce a variety of side effects. At the very least, you should be confident that taking them is better than not taking them.
Unfortunately, for many patients, many psychiatric medications do not produce significant benefits; furthermore, doing nothing or taking over-the-counter elixirs can sometimes produce astonishing benefits. If only someone found a way to discover novel psychiatric drugs and then conclusively demonstrate their effectiveness. I can assure you that many pharmaceutical companies around the world have been spending small fortunes trying to do exactly that. This is the problem.
Psychiatric drug development programs have demoralizingly low success rates. The success rate is especially bad during the last phases of testing when the drug’s effectiveness is being compared to a placebo pill. Overall, psychiatric medications are among the least successful of all drug investigations. Why?
The answer is simple: these drugs are designed to influence the function of the brain, which is, of course, the organ responsible for demonstrating the symptoms of psychiatric illness. Essentially, the biggest hurdle for the discovery of novel and effective psychiatric medications is the brain’s ability to generate a significant placebo effect.
Too often in clinical trials, new drugs fail due to a lack of efficacy as compared to the placebo treatment. The placebo effect is especially strong for two specific brain conditions, the experience of pain and mood. Essentially, if you think that a drug will take away pain, it probably will (at least somewhat); if you think that a drug will make you happier, it probably will (at least somewhat). Psychiatric patients, regardless of their diagnosis, often experience chronic body aches along with depression.
Thus, it is not surprising that recent clinical studies have reported that the placebo response is particularly large in major depressive disorder (up to 50%!) and schizophrenia (up to 25%). Furthermore, for reasons that no one can yet explain, the placebo response rate has been steadily increasing over the past several decades.
Unfortunately, our amazing ability to imagine ourselves mentally healthy (and mentally unhealthy, it works both ways) has made it more difficult to prove that new psychiatric drugs are effective, as compared to placebo. This is a central reason behind the decision of several pharmaceutical companies to reduce or even close their psychiatric research and development programs. It simply became too expensive to continue trying to prove that a new drug was better than the placebo.
The problem is made worse by the discovery that at the same time that the placebo effect has been increasing, the nocebo effect, which refers to undesirable effects following administration of placebo treatments, are also significantly greater in drug trials for psychiatric drugs. Thus, adherence to the medication and withdrawal rates are also negatively impacting investigations for new and effective psychiatric medications.
A recent study designed a way to systematically address key factors associated with enhanced placebo response. It is called the Placebo-Control Reminder Script. Essentially, prior to and throughout the study, the subjects are read a brief passage that provides information about factors that might amplify their placebo response, including expectation biases and common misunderstandings about the purpose of placebo trials (no one likes to know that they are receiving the sugar pill!), as well as other potential biases and misconceptions when reporting their symptoms.
The goal is to enable participants to serve as more impartial reporters of their symptoms and thus minimize factors that might enhance the placebo and nocebo responses. Hopefully, the introduction of the Placebo-Control Reminder Script into future study designs will lead to the discovery of effective and safe psychiatric medications.
© Gary L. Wenk, Ph.D., author of Your Brain on Food (3rd Ed, Oxford University Press).
References
Cohen EA et al., Placebo response mitigation with a participant-focused psychoeducational procedure: a randomized, single-blind, all placebo study in major depressive and psychotic disorders. Neuropsychopharmacology (2021) 46:844–850; https://doi.org/10.1038/s41386-020-00911-5
