Placebo effect, antidepressants not responsible for improvement in depression

In a study of fluoxetine (Prozac) for teenagers, researchers found that the placebo effect predicted good outcomes, but the actual drug treatment did not. After taking into account the treatment bias (people who learned they were receiving the intervention rather than a placebo), the drug was not effective in treating depression.

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

The researchers wrote that treatment outcomes are strongly predicted and may increase the effectiveness of the drug in the absence of actual effects.

That is, the researchers write that the drug is not actually effective in the treatment of depression (absence of real effects), but is felt it believed by researchers to be effective because the results were contaminated by the placebo effect.

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

The current study was authored by John Giordini, Julie Clough, Natalie Aboustat and Melissa Raven at the University of Adelaide, Australia, and Joanna Moncrieff at University College London, UK. Posted in Australian and New Zealand Journal of Psychiatry. Giurdini has been interviewed by Mad in America about her work on the lack of evidence base for psychiatric treatments, including antidepressant medications, for children and adolescents. Moncrief has also been interviewed by Mad in America, and was the lead author of the 2022 study that put the final nail in the coffin of the chemical imbalance myth of depression.

Fluoxetine is the only FDA-approved antidepressant for use in children and adolescents. Nonetheless, its effectiveness has been questioned, with it even being known to increase the risk of suicide in children. A recent study found a three-fold increase in the risk of suicide and another study found that the risk may be up to six times higher. Even in adults, antidepressant medications can double the risk of suicide.

placebo-controlled study

In placebo-controlled studies, a group that receives an intervention is compared with a group that does not receive the intervention. But the people in that control group have been given Some? (placebo) that makes them think they have received the intervention. Having this group helps researchers find out some things. For example, one is that people can improve naturally without the intervention, so having a control group that does not receive the intervention allows researchers to compare the intervention to the natural improvement that people make over time. Experience with.

But another thing that the placebo group controls is the placebo effect, which is that people improve when they faith That they received treatment, whether they actually received treatment or not. A key feature of this type of study is blinding, which is a term for keeping participants, researchers, and/or treating physicians in the dark about whether the subject received the treatment or not. The aim is to equalize the two groups: if one does not know whether they received the treatment or not, the effects should be consistent throughout the study.

Unfortunately, in this type of study, the curtain is often broken. One aspect that can easily break blinding is adverse effects: people know the potential side effects of the drug, so if they experience those effects, they can guess that they are probably in the treatment group, not the other. In the placebo group. People who anticipate that they are receiving the treatment are likely to have an increased placebo effect so that they perform better expect To do better. Additionally, people who assume they received a placebo are likely to feel worse because they know they did not receive the real treatment.

But how much of an impact those estimates have, and whether the placebo effect is stronger than the actual efficacy of the treatment, is different for every study, treatment, and condition.

current study

In 2003, the NIMH-sponsored Treatment for Adolescents with Depression Study (TADS) included 439 adolescents aged 12–17 who met DSM-IV criteria for depression. There were four treatment arms, which included only fluoxetine (Prozac); cognitive-behavioral therapy (CBT) alone; Fluoxetine and CBT; And placebo. The psychotherapy groups could not be blinded. The randomized trial ran for 12 weeks, and participants were asked which group they were in at both 6 weeks and 12 weeks. Improvement in depression was measured with the Children’s Depression Rating Scale (CDRS-R).

The TADS study is commonly cited as evidence of the effectiveness of Prozac in the treatment of depression, as the combined drug and CBT group performed slightly better than the placebo group. However, the drug alone group did not outperform the placebo group in the TADS analysis of the CDRS-R.

The current analysis was conducted as part of the Restoring Invisible and Abandoned Trials (RIAT) initiative, which allowed researchers access to raw data from the TADS study. They also obtained information about the fluoxetine group (109 participants) and the placebo group (111 participants), as they were two blinded groups, so that the effects of unblinding could be compared directly.

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

The researchers found that the placebo effect was stronger than the actual treatment. Those who guessed they received the treatment were more likely to improve than those who guessed they received a placebo.even if their guess is wrong, That is, on average, people who believed they received the drug improved, even if they actually received a placebo. Similarly, people who believed they received a placebo were less likely to improve, even if they actually received the drug.

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

Surprisingly, the group that performed best were those who believed they received the drug, but actually received placebo, These patients did better Compared to those who received the drug and knew it!

The researchers wrote that teens who guessed they were on fluoxetine but were actually given a placebo showed the greatest improvement on the CDRS-R.

Finally, the researchers confirmed TADS’s initial finding: After accounting for the placebo effect (treatment estimate), the researchers found that taking Prozac did not improve depression.

The treatment estimate had a substantial and statistically significant effect on the outcome (Children’s Depression Rating Scale-Revised mean difference in change 9.12, = 0.334, P < 0.001), but not the actual treatment arm (1.53), the researchers write. [2.83; 5.89]= 0.056, p = 0.489).

Researchers have concluded that unblinding, which increases the placebo effect, may be the reason why antidepressants usually beat placebos by small margins in clinical trials. They say future studies need to assess unblinding to be sure to provide accurate data on the drug’s efficacy.

Our analysis suggests that the effects demonstrated in placebo-controlled trials of antidepressants may represent amplified placebo effects, which are the result of differential distribution of expectancy effects caused by unblinding. Since expectancy effects are substantial, even a small amount of unblinding can produce a noticeable difference between an active drug and placebo. For future research, there is a clear need for more rigorous study designs that systematically record and analyze treatment estimates and assess blinding, and do so early and frequently, they write.

Furthermore, since clinical practice guidelines are based on evidence from studies such as TADS, researchers argue that guideline authors need to reevaluate the evidence base for their recommendations. Recommending antidepressants based on studies like TADS is bad science.

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


Giurdini, J., Moncrieff, J., Clough, J., Aboustat, N., and Raven, M. (2023). Treatment estimates in treatment studies for depressed adolescents: Accuracy, clarity, and effects on outcomes. Australian and New Zealand Journal of Psychiatry. Published online December 21, 2023. (full text)

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