Many people have tried to figure out why, some almost going to the extent of seeing some kind of mystical explanation to it. The most common and accepted explanation is to say that clinical investigators are becoming less and less experienced and are responsible for this. The theory is that if an investigator is too empathetic during a clinical trial, they might trigger a higher Placebo Response in the subject. In addition, if the investigator is not properly trained they might be responsible for inaccurate assessments.
I believe that the explanation is actually easier to figure out. As a clinical investigator myself, some might say that I am biased but I also believe myself to be more knowledgeable than mot people about this subject since I am writing about something I experience first hand.
It is my strong belief that the rise of the Placebo Response in recent CNS clinical trials is due to the rise of regulatory and legal pressure. Let me explain this. Pharmaceutical companies are responsible for the clinical trials that they conduct (investigators too of course). Regulatory agencies put a lot of pressure on Pharmaceutical Companies to prove the efficacy of their new treatments. Statistically speaking, if you want to prove the efficacy of a new agent, you have to conduct trials v. placebo and v. the most up-to-date treatment used in the same indication. In order to do so, subjects enrolled in clinical trials have to be "perfect" in the sense that the less concomitant medical condition and treatment they have the better. Following this logic, subjects enrolled in antidepressant trials seldom suffer from any other medical condition, they are not allowed to take other medicine for anxiety or sleeping disorder and most importantly they won't enter the trial if they have suicidal ideations.
This is where the explanation lies: the most severely depressed patients all have suicidal ideations, they all suffer from severe insomnia and anxiety that would require concomitant treatment. Therefore, they wouldn't be enrolled in CNS clinical trials. The only consequence to this is that only less severely depressed patients are enrolled in clinical trials and they are the ones that are the most likely to show Placebo response.
I understand that in order to statistically prove the efficacy of a new agent, it has to be taken by patients with no other concomitant medication. However, the reality is that enhancing to statistical "beauty" of a trial by not allowing concomitant medication leads to enrolling patients that are not heterogenous enough to differentiate the new agent from the Placebo.
In addition, pharmaceutical companies don't want investigators to enroll patients that are at suicidal risks because the legal consequences of a suicide would be devastating. Once again, I understand their reasons but the reality is that it leads to enrolling less severely depressed patients in CNS clinical trials, therefore leading to a higher rate of Placebo responders.
Authorities and Pharmaceutical Companies really need to consider this in the future before they start putting the blame on investigators that, on top of everything, are probably better trained than ever before. In essence, when pharmaceutical companies say that investigators are responsible for the rise of the Placebo Response, they are admitting that patients enrolled in their trials are very likely to show Placebo Response and it has been know for a very long time, that depressed patients very likely to react to external circumstances are usually the least severely depressed ones, hence proving my point!
