In a study of fluoxetine (Prozac) in adolescents, researchers found that the placebo effect predicted good outcomes, but not the drug treatment itself. After accounting for “treatment assumptions” (those who understood they were receiving an intervention rather than a 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 assumes strongly predicted outcomes and may have led to an exaggeration of the drug’s effectiveness in the absence of real effects,” the researchers write.
In other words, the researchers write that the drug is not really effective in treating depression (“lack of real effects”) but that it is perceived effective by the researchers because the results were contaminated by the placebo effect.
This finding is similar to another recent finding, which referred to the placebo effect as “subjective beliefs.” In this 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 outcomes, but actual use of the devices was not, compared to placebo. (In a fourth study, belief was a significant predictor of outcome, as was the treatment itself.)
This study was authored by Jon Jureidini, Julie Klau, Natalie Aboustate and Melissa Raven of the University of Adelaide, Australia, and Joanna Moncrieff of University College London, UK. It was published in the Australian and New Zealand Journal of Psychiatry. Jureidini was interviewed by Mad in America about his work on the lack of evidence for psychiatric treatments, including antidepressants 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 antidepressant approved by the FDA for use in children and adolescents. Nevertheless, its effectiveness has been questioned, although it is known to increase the risk of suicide in children. A recent study found that the risk of suicide increased threefold 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, the group that receives an intervention is compared to a group that does not receive it. But those in this control group receive something (the placebo) which makes them believe that they have received the intervention. The creation of this group allows researchers to take several elements into account. For example, the first is that people can get better naturally, without intervention, so having a control group that doesn’t receive the intervention allows researchers to compare the intervention to the natural improvement people experience over time .
But another thing the placebo group controls is the placebo effect: people get better when they believe that they received treatment, whether they actually did so 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 as to whether or not the subject received the treatment. The goal is to equalize the two groups: if no one knows whether they received the treatment, then the effect should be consistent throughout the study.
Unfortunately, in this type of study, the blind is often broken. Side effects are one aspect that can easily break the blindness: people know the potential side effects of the drug, so if they experience these effects, they can guess that they are probably in the treatment group and not the placebo group . Those who believe they are receiving the treatment will likely have an increased placebo effect, that is, they will perform better because they to wait for do better. At the same time, those who think they received the placebo may have worse outcomes because they know they did not receive the actual treatment.
But the impact of these assumptions and the question of 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 Adolescents with Depression Study (TADS) included 439 adolescents ages 12 to 17 who met DSM-IV criteria for depression. There were four treatment groups, including only fluoxetine (Prozac); cognitive behavioral therapy (CBT) only; fluoxetine and CBT; and placebo. The psychotherapy groups could not be blinded. The randomized trial lasted 12 weeks and participants were asked which group they thought they were in at 6 weeks and 12 weeks. Improvement in depression was measured using the Child Depression Rating Scale-Revised (CDRS-R).
The TADS study is commonly cited as evidence of Prozac’s effectiveness in treating depression, as the combined drug-CBT group performed slightly better than the placebo group. However, the drug-alone group did not perform better than 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 study. They obtained information on the fluoxetine group (109 participants) and the placebo group (111 participants), since these were both blinded groups, in order to directly compare the effects of unblinding.
Across all groups, more than 60% of participants and evaluators correctly guessed whether they had received the drug or the placebo (a perfectly blinded study would result in 50% of people guessing correctly).
The researchers found that the placebo effect was stronger than the treatment itself. Those who thought they received the treatment were more likely to improve than those who thought they received the placebo.even if their assumption was incorrect. That is, on average, those who thought they received the drug improved, even though they actually received the placebo. Likewise, those who thought they had received the placebo were less likely to see their condition improve, even if they actually received the drug.
Those who thought they had received the drug, on average, improved their CDRS-R score by 10 points more than those who thought they had received the placebo. Those who thought they received the drug improved by 26.98 points on average. Those who thought they had received the placebo improved by 16.65 points on average.
Surprisingly, the group that performed best was the one who believed they had received the drug, but actually received the placebo. These patients did better than those who received the medicine and knew it!
“Adolescents who thought they were taking fluoxetine, but were actually assigned to placebo, demonstrated the greatest improvement in the CDRS-R,” the researchers write.
Finally, the researchers confirmed the initial results of the TADS: after taking into account the placebo effect (treatment estimation), the researchers found that taking Prozac did not improve depression.
The researchers write: “Treatment assumption had a substantial and statistically significant effect on outcomes (Children’s Depression Rating Scale-Revised Mean Difference in Change 9.12, β = 0.334, p < 0.001) , but this is not the case for the actual treatment arm (1.53 (−2.83; 5.89). ), β = 0.056, p = 0.489).
The researchers conclude that unblinding, which amplifies the placebo effect, may be the reason why antidepressants usually slightly beat placebo in clinical trials. They add that future studies must be sure to evaluate unblinding in order to provide accurate data on the effectiveness of the drugs.
“Our analysis suggests that the effects demonstrated in placebo-controlled trials of antidepressants may represent amplified placebo effects that result from the differential distribution of life expectancy effects caused by unblinding. Because the effects on life expectancy are substantial, even a small degree of unblinding could produce 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 record and analyze treatment assumptions and assess blindness, early on and repeatedly,” they write.
Additionally, because clinical practice guidelines are based on evidence from studies like TADS, researchers say guideline authors need to re-evaluate the evidence base on which their recommendations are based. Recommending antidepressants based on studies like TADS is bad science.
Indeed, the evidence for antidepressants – even for adults – is so poor that a recent article, authored by more than 30 leading figures in the field, recommends against their use in all but “the most severe” depressions. serious”. Guidelines from the World Health Organization (WHO) agree: “Antidepressant medications are not necessary for mild depression,” according to the WHO. There are many other approaches, with fewer side effects, but just as effective.
Jureidini, J., Moncrieff, J., Klau, J., Aboustate, N. and Raven, M. (2023). Treatment assumptions in the Adolescent Depression Treatment Study: Accuracy, unblinding, and influence on results. Australian and New Zealand Journal of Psychiatry. Published online December 21, 2023. https://doi.org/10.1177/0004867423121862 (Full text)
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