In a study of fluoxetine (Prozac) in adolescents, researchers found that the placebo effect predicted good outcomes, but the actual drug treatment did not. After controlling for treatment conjecture (those who realized they were getting the intervention rather than the placebo), the drug was not effective in treating depression.
In fact, those who received a placebo but thought they were receiving Prozac improved more than those who received the drug and knew it.
The treatment strongly guesses the predicted outcomes and may have led to an exaggeration of the effectiveness of the drugs without real effects, the researchers write.
In other words, the researchers write that the drug is not actually effective in treating depression (absence of real effects), but is detected researchers are effective because the results were contaminated by the placebo effect.
This finding is similar to another recent finding that referred to placebo as subjective beliefs. In that article, researchers found that participants in three different studies on the neuromodulation of depression 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 the fourth study, faith was a significant predictor of outcome, but so was the actual treatment.)
The current study was written by Jon Jureidini, Julie Klau, Natalie Aboustate and Melissa Raven from the University of Adelaide, Australia, and Joanna Moncrieff from University College London, UK. It was published in Australian & New Zealand Journal of Psychiatry. Mad in America interviewed Jureidin about her work on the lack of evidence for psychiatric treatments, including anti-depressants for children and adolescents. Moncrieff was also interviewed by Mad in America and was the lead author of a 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 children and adolescents. Nevertheless, its effectiveness has been questioned, although it is known to increase the risk of suicide in children. One recent study found a threefold increased risk of suicide, and another study found that the risk could be up to six times higher. Even in adults, antidepressants can double the risk of suicide.
In placebo-controlled studies, a group that receives an intervention is compared to a group that does not. But those in that control group are given something (placebo) that makes them think they have received the intervention. This group allows researchers to consider a couple of things. For example, one is that people can heal naturally without intervention, so if a control group receives no intervention, researchers can compare the intervention to the natural healing that people experience over time.
But the other thing that the placebo group controls is the placebo effect that people get better believe that they have received treatment, whether they actually did or not. A key feature of such research is blinding, a term used to keep participants, researchers, and/or medical staff in the dark as to whether a subject has received treatment or not. This is to equalize the two groups: if no one knows whether they received the treatment, the effect should be consistent throughout the study.
Unfortunately, the blind is often broken in these types of studies. One aspect that can easily break the blind is adverse effects: people know the possible side effects of the drug, so if they experience these effects, they can guess that they are likely to be in the treatment group, not the placebo group. Those who guess they are getting treatment are likely to have an enhanced placebo effect to make them feel better because they expect to do better. At the same time, those who think they got a placebo are likely to feel worse because they know they didn’t get the real treatment.
But how much influence these guesses have, and whether the placebo effect is stronger than the true effect of the treatment, is different for each study, treatment, and condition.
In 2003, the NIMH-sponsored Treatment for Adolescent Depression Study (TADS) included 439 youth aged 12–17 who met DSM-IV criteria for depression. There were four treatment groups, including fluoxetine (Prozac) only; cognitive-behavioral therapy (CBT) only; fluoxetine and CBT; and placebo. Psychotherapy groups could not be blinded. The randomized trial lasted 12 weeks, and participants were asked which group they believed they belonged to at both 6 weeks and 12 weeks. Improvement in depression was measured with the Childrens Depression Rating ScaleRevised (CDRS-R).
The TADS study is commonly cited as evidence of Prozac’s effectiveness in treating depression, as the combined drug and CBT group fared 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 to access raw data from the TADS trial. They obtained information about the fluoxetine group (109 participants) and the placebo group (111 participants), as these were the two blinded groups in order to directly compare the effects of unblinding.
In all groups, more than 60% of participants and raters correctly guessed whether they were receiving drug or placebo (a fully blinded study would result in 50% correct guesses).
The researchers found that the placebo effect was stronger than the treatment itself. Those who guessed they would get treatment were more likely to get better than those who guessed they would get a placeboeven though their guess was wrong. That is, on average, those who believed they were receiving the drug got better, even though they were actually receiving a placebo. Similarly, those who believed they had received a placebo were less likely to improve even if they had actually received the drug.
Those who believed they had received the drug improved an average of 10 points more on the CDRS-R than those who believed they had received a placebo. Those who believed they had received the drug improved by an average of 26.98 points. Those who believed they had received a placebo improved by an average of 16.65 points.
Amazingly, the group that did best were those who believed they had received the drug, but actually received a placebo. These patients did better than those who received the medicine and knew it!
The researchers write that youth who thought they were getting fluoxetine but were actually given a placebo showed the greatest improvement on the CDRS-R.
Finally, the researchers confirmed the TADS’ original finding: after taking into account the placebo effect (the treatment guess), the researchers found that taking Prozac did not improve depression.
The researchers write that the treatment guess had a significant and statistically significant effect on the outcome (Children’s Depression Rating Scale-Revised change mean difference 9.12 , = 0.334, p < 0.001), but the actual treatment group did not (1.53) [2.83; 5.89]= 0.056, p = 0.489).
The researchers conclude that unblinding, which strengthens the placebo effect, may be why antidepressants typically outperform placebos in clinical trials. They add that future studies need to ensure unblinding to provide accurate data on drug efficacy.
Our analysis suggests that the effects shown in placebo-controlled studies of antidepressants may represent increased placebo effects resulting from a different distribution of expectancy effects due to unblinding. Because expectancy effects are substantial, even a small unblinding may cause an apparent difference between active drug and placebo. Future research clearly needs more rigorous study designs that systematically record and analyze treatment guesses and assess blinding, and do so early and repeatedly, they write.
Furthermore, because clinical practice guidelines are based on evidence from studies such as TADS, researchers argue that guideline authors need to reassess the evidence for recommendations. Recommending antidepressants based on studies like TADS is bad science.
Even for adults, the evidence for antidepressants is so weak that a recent paper, written by more than 30 prominent people in the field, recommends their use in all but the most severe depression. The guidelines of the World Health Organization (WHO) agree: according to the WHO, antidepressants are not needed for mild depression. There are many other approaches with fewer side effects that are just as effective.
Jureidini, J., Moncrieff, J., Klau, J., Aboustate, N. and Raven, M. (2023). Treatment guesswork in adolescent depression research: accuracy, unblinding, and impact on outcomes. Australian & New Zealand Journal of Psychiatry. Published online 21 December 2023. https://doi.org/10.1177/0004867423121862 (full text)
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