Quoting Steven Hollon, in his book The Emperor’s New Drugs, Irving Kirsch said it was a “dirty little secret” that there was only a small difference between the experimental and control groups for the patients who participated in the randomized clinical trials (RCTs) used to approve SSRIs. Be sure to get this: the pharmaceutical companies that produced the drugs AND the regulatory agencies that approved them, knew there was essentially no difference between the effects of the drug and the placebo. Yet the drugs were approved for use with humans. “Many have long been unimpressed by the magnitude of the differences observed between treatments and controls, what some of our colleagues refer to as the ‘dirty little secret’ in the pharmaceutical literature.”

Kirsch was originally interested in studying the placebo effect, and not the antidepressant drug effect. “How is it, I wondered, that the belief that one has taken a medication can produce some of the effects of that medication?” He was not surprised to find a substantial placebo effect of the medications on depression. But he was surprised to see how small the drug effect was. “Seventy-five percent of the improvement in the drug group also occurred when people were give dummy pills with no active ingredient in them.”

You can read an article by Kirsch describing the research process described here in: “Antidepressants and the Placebo Effect.”

He replicated the findings in another study published in 2002, using the data submitted to the FDA by the pharmaceutical companies in their process of obtaining approval for six new generation antidepressants. There were some advantages to using the FDA data set. First, they received data on the published and unpublished clinical trials conducted by the pharmaceutical companies. What was particularly important here was that: “The results of the unpublished trials were known only to the drug companies and the FDA, and most of them failed to find a significant benefit of drug over placebo.”

A second advantage was that the FDA trials all used the same primary measure of depression—the Hamilton depression scale (HAM-D). The third advantage was that the FDA data was the same data used for the approval of the medications. So if there had been anything wrong with the trials, one would think, the medications would not have been approved.

In the data sent to us by the FDA, only 43% of the trials showed a statistically significant benefit of drug over placebo. The remaining 57% were failed or negative trials. . . . The results of our analysis indicated that the placebo response was 82% of the response to these antidepressants.

One explanation for Kirsch’s results could be that the replication done in 2002 contained both the published and unpublished clinical trials. The inclusion of failed and negative trials would have lowered the positive results required by the FDA for approval of a medication. So the placebo response was greater in this replication than it was in their original study because of including the unpublished trials. Nevertheless, the majority of the trials failed to show positive results. Remember that the pharmaceutical companies themselves conducted these studies; and that they were the trials done in the process of gaining approval for their medications.

Getting approval of a drug by the FDA requires the submission of two studies showing the new drug is better than a placebo. It doesn’t matter if it takes you ten studies to get those two; only the two positive ones count for approval. The requirement is that two trials have to demonstrate the drug is more effective than a placebo, and that measurement has to be statistically significant. Kirsch’s analysis found just a 1.8-point difference on the HAM-D scale between drug and placebo—a difference that is not clinically significant, even though it may be statistically significant. The National Institute for Health and Clinical Excellence (NICE) has set the criterion for a clinically significant difference between drug and placebo to be at least three points on the HAM-D scale.

A criticism of Kirsch’s 2002 study was that the results were based on clinical trials conducted on subjects who were not very depressed. So Kirsch et al. (2008) reanalyzed the data in: “Initial Severity and Antidepressant Benefits.” They found that “the overall effect of new-generation antidepressant medications is below recommended criteria for clinical significance.” Only for the most extremely depressed patients was there evidence for clinical significance, according to the HAM-D scale. Yet they also concluded this difference was “due to a decrease in the response to placebo rather than an increase in the response to medication.”

So the question becomes, what do all these drugs have in common that gives them a slight, but statistically significant effect on depression over placebo? The answer is that they all produce side effects.

Clinical trials are all double-blind studies, meaning that neither the patient nor the doctor is supposed to know whether the patient is given the active drug or the placebo. Yet in one study, 80% of patients guessed correctly whether or not they were on the drug or placebo; and 87% of doctors also guessed correctly. So most patients and most doctors could break the blind by guessing according to the presence or absence of side effects to the medications. Additionally, “89% of the patients in the drug group correctly ‘guessed’ that they had been given the real antidepressant, a result that is very unlikely to be due to chance.”

So clinical trials are not really double blind studies if most patients can guess whether or not they have been given the real drug rather than the placebo. This ability to “break blind” has been known in the research literature since 1986 when Rabkin et al. published their study, “How Blind is Blind” in the September issue of Psychiatry Research. Yet drug trials continue to use inert placebos.

But what would happen if an active placebo were used in clinical trials? Active placebos have been used with antidepressants in other studies. See “Active Placebos Versus Antidepressants for Depression.”  Moncrieff et al. reported that: “differences between antidepressants and active placebos were small.” Kirsch noted that in the nine clinical trials discussed by Moncrieff et al. where an active placebo (atropine) was used, there was only a significant difference in two of the studies.

In the vast majority (78 percent) of the clinical trials in which active placebos were used, no significant differences were found between the drug and the placebo. So comparisons with inactive placebos are much more likely to show drug-placebo differences than comparisons with active placebos. This suggests that at least part of the difference that has been found between antidepressant and placebo may be due to the experience of more side effects on the active drug than on the placebo.

It’s good this dirty little secret is becoming more widely known. But unfortunately the horse has already left the barn. Too bad it wasn’t getting press fifteen years ago before the SSRIs started going off-patent. The pharmaceutical companies have already gouged the public with their SSRI profits and their drugs have gone generic.

Eli Liliy’s Prozac went off patent in 2001. GlaxoSmithKline’s Paxil has been off-patent since 2003. Forest Labs’ Celexa patent expired in 2003. Pfizer’s Zoloft patent expired in 2006. Wyeth’s Effexor (now marketed by Pfizer) went off-patent in 2006. Wellbutrin, developed by Burroughs Wellcome and later acquired by GlaxoSmithKline, lost its patent in 2006. Lexapro was developed by Forest Laboratories in conjunction with Lundbeck and they won two patent extensions. But it lost exclusivity in 2012.