Placebo Effect Not Antidepressants Responsible for Improving Depression

In a study of fluoxetine (Prozac) for adolescents, researchers found that the placebo effect predicted good outcomes, but the actual drug treatment did not. After accounting for treatment prediction (those who thought they were receiving an intervention rather than a placebo), the drug was ineffective in treating depression.

In fact, those who received a placebo but thought they had received Prozac improved more than those who received the drug and knew it.

The treatment strongly predicted outcomes and could lead to an exaggeration of the drug’s effectiveness in the absence of actual effects, the researchers wrote.

That is, the researchers wrote that the drug is not actually effective in treating depression (the absence of actual effects) but realized to be effective by researchers because the results are contaminated by the placebo effect.

This finding is similar to another recent finding, which refers to the placebo effect as subjective beliefs. In that article, researchers found that in three different studies of neuromodulation for depression, participants beliefs that they would improve after using the devices was a significant predictor of outcome, but actual use of the devices was not, compared to placebo. (In a fourth study, belief was a significant predictor of outcome, but so was actual treatment.)

The current study was written by Jon Jureidini, Julie Klau, Natalie Aboustate, and Melissa Raven at the University of Adelaide, Australia, and Joanna Moncrieff at University College London, UK. It was published in Australian and New Zealand Journal of Psychiatry. Jureidini was interviewed by Mad in America about his work on the lack of evidence base for psychiatric treatments, including antidepressants for children and adolescents. Moncrieff was also interviewed by Mad in America, and was the lead author on a 2022 study that put the final nail in the coffin of the chemical imbalance myth of depression.

Fluoxetine is the only antidepressant approved by the FDA for use in children and adolescents. However, its effectiveness has been questioned, even though it is known to increase the risk of suicide in children. A recent study found a threefold increase in suicide risk and another study found the risk could be as high as six times greater. Even in adults, antidepressants can double the risk of suicide.

Placebo-Controlled Studies

In placebo-controlled studies, the group receiving the intervention is compared to a group that does not. But those in the control group were given one thing (the placebo) making them think they received the intervention. Having this group allows researchers to account for several things. For example, one is that people improve naturally, without intervention, so having a control group that does not receive the intervention allows researchers to compare the intervention to the natural improvement that people experience over time. of time.

But another thing that the placebo group controlled for was the placebo effect that makes people feel better when they believe that they received a treatment, whether they actually did or not. A key feature of this type of study is blinding, a term for keeping participants, researchers, and/or treatment clinicians in the dark about whether or not the subject received the treatment. This is intended to equalize the two groups: if no one knows whether they received the treatment, the effect should be consistent throughout the study.

Unfortunately, in this type of study, the blind is often broken. One aspect that is easily blinded is adverse effects: people know the potential side effects of the drug, so if they are experiencing those effects, they can guess that they are likely to be in the treatment group, not the placebo group. Those who predict that they will receive treatment are likely to have an enhanced placebo effect to feel better because they are expect to do better. At the same time, those who guessed they had received a placebo were likely to do worse because they knew they had not received the actual treatment.

But how much effect those predictions have, and whether the placebo effect is stronger than the actual effectiveness of the treatment, is different for each study, treatment, and condition.

The Current Study

In 2003, the NIMH-sponsored Treatment for Adolescent Depression (TADS) included 439 youth ages 12-17 who met DSM-IV criteria for depression. There are four treatment medications, including fluoxetine (Prozac) alone; cognitive-behavioral therapy (CBT) only; fluoxetine and CBT; and placebo. The psychotherapy groups were not blinded. The randomized trial lasted 12 weeks, and participants were asked which group they believed they were in at both 6 weeks and 12 weeks. Improvement in depression was measured using the Childrens Depression Rating ScaleRevised (CDRS-R).

The TADS study is commonly cited as evidence for the effectiveness of Prozacs in treating depression, as the combined drug and CBT group did slightly better than the placebo group. However, the drug alone group did no better than the placebo group on the TADS test of the CDRS-R.

The current analysis was conducted as part of the Restoring Invisible and Abandoned Trials (RIAT) initiative, which allowed researchers to access raw data from the TADS study. They obtained information on the fluoxetine group (109 participants) and the placebo group (111 participants), since those were the two groups that were blinded, to directly compare the effects of not being blinded.

In all groups, more than 60% of participants and raters correctly guessed whether they received the drug or placebo (a fully blinded study would result in 50% correct guesses).

Researchers have found that the placebo effect is stronger than the actual treatment itself. Those who predicted they received the treatment were more likely to improve than those who predicted they received the placeboeven if their guess is wrong. That is, on average, those who believed they received the drug got better, even though they actually received a placebo. Also, those who believed they received the placebo were more likely to improve, even if they actually received the drug.

Those who believed they received the drug, on average, improved 10 points more on the CDRS-R than those who believed they received the placebo. Those who believed they had received medication improved by 26.98 points, on average. Those who believed they received a placebo improved by 16.65 points, on average.

Remarkably, the group that did the best were those who believed they had received the drug, but actually received a placebo. These patients did better than those who received medicine and knew it!

Adolescents who were predicted to be on fluoxetine, but were actually allocated placebo, showed the greatest improvement on the CDRS-R, the researchers wrote.

Finally, the researchers confirmed the first TADS finding: after accounting for the placebo effect (prediction of treatment), the researchers found that taking Prozac did not improve depression.

The researchers wrote, Treatment prediction had a large and statistically significant effect on outcome (Childrens Depression Rating Scale-Revised change mean difference 9.12, = 0.334, p < 0.001), but the actual treatment arm did not (1.53 ). [2.83; 5.89]= 0.056, p = 0.489).

The researchers concluded that unblinding, which magnifies the placebo effect, may be why antidepressants usually beat placebo by a slight margin in clinical trials. They added that future studies need to ensure that unblinding is assessed in order to provide accurate data on the drug’s effectiveness.

Our analysis suggests that the effects shown in placebo-controlled trials of antidepressants may represent enhanced placebo effects that result from differential hope effects caused by unblinding. Because the effects of dependence are large, even a small degree of unblinding can cause an apparent difference between an active drug and a placebo. For future research, there is a clear need for more rigorous study designs that systematically document and evaluate treatment predictors and assess blindness, and do so early and repeatedly, they write.

Moreover, because clinical practice guidelines are based on evidence from studies such as TADS, the researchers argued that guideline authors need to re-evaluate the evidence base for their recommendation. Recommending antidepressants based on studies like TADS is not good science.

In fact, the evidence base for antidepressants even for adults is so weak that a recent article, written by 30+ prominent people in the field, recommends against their use in all but the most severe depression. World Health Organization (WHO) guidelines agree: Antidepressant drugs are not needed for mild depression, according to the WHO. There are many other techniques, with fewer side effects, that are just as effective.


Jureidini, J., Moncrieff, J., Klau, J., Aboustate, N., & Raven, M. (2023). Treatment predictors in the Depressed Youth Treatment Study: Accuracy, unblinding and influence on outcomes. Australian and New Zealand Journal of Psychiatry. Published online December 21, 2023. (Full Text)

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