Placebo Effect—Not Antidepressants—Responsible for Depression Improvement

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

15
14623

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 guess” (those who figured out that they were receiving an intervention rather than placebo), the drug was not effective in depression treatment.

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

“Treatment guesses strongly predicted outcomes and may have led to the exaggeration of drug effectiveness in the absence of actual effects,” the researchers write.

That is, the researchers write that the drug is not actually effective in depression treatment (“the absence of actual effects”) but is perceived to be effective by the researchers because the results were contaminated by the placebo effect.

3D render of placebo pills isolated over wood background

This finding is similar to another recent finding, which referred 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 the actual use of the devices was not, compared to placebo. (In a fourth study, belief was a significant predictor of outcome, but so was the actual treatment.)

The current study was authored 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 the Australian & New Zealand Journal of Psychiatry. Jureidini has been interviewed by Mad in America about his work on the lack of evidence base for psychiatric treatments, including antidepressants for children and adolescents. Moncrieff has also been 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 FDA-approved antidepressant for use in children and adolescents. Nonetheless, its effectiveness has been questioned, even as it is known to increase the risk of suicide in kids. One recent study found a threefold increase in suicide risk and another study found that the risk may be as high as six times greater. Even in adults, antidepressants may double the risk of suicide.

Placebo-Controlled Studies

In placebo-controlled studies, the group that receives an intervention is compared to a group that does not. But those in that control group are given something (the placebo) that makes them think they have received the intervention. Having this group allows researchers to account for a couple of things. For instance, one is that people may get better naturally, without an intervention, so having a control group that doesn’t receive the intervention allows researchers to compare the intervention to the natural improvement that people experience over time.

But another thing the placebo group controls for is the placebo effect—that people improve when they believe that they have received a treatment, whether they actually did or not. A key feature of this kind of study is blinding, a term for keeping participants, researchers, and/or treatment clinicians in the dark about whether the subject received the treatment or not. This is intended to equalize the two groups: if no one knows whether they received the treatment, then the effect should be consistent across the whole study.

Unfortunately, in this type of study, the blind is often broken. One aspect that can easily break the blind 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 placebo group. Those who guess that they are receiving the treatment are likely to have an enhanced placebo effect—to do better because they expect to do better. At the same time, those who guess they received the placebo are likely to do worse because they know they did not receive the actual treatment.

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

The Current Study

Back 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, including fluoxetine (Prozac) only; cognitive-behavioral therapy (CBT) only; fluoxetine and CBT; and placebo. The psychotherapy groups were not able to be blinded. The randomized trial lasted for 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 with the Children’s Depression Rating Scale–Revised (CDRS-R).

The TADS study is commonly cited as evidence for Prozac’s effectiveness in depression treatment, because the combined drug and CBT group did slightly better than the placebo group. However, the drug group alone did no 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 the researchers access to the 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 blinded groups, in order to directly compare the effects of unblinding.

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

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

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

Amazingly, the group that did the best was those who believed they received the drug, but actually received the placebo. These patients did better than those who received the drug and knew it!

“Adolescents who guessed they were on fluoxetine, but were actually allocated to placebo, demonstrated the largest improvement in CDRS-R,” the researchers write.

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

The researchers write, “Treatment guess had a substantial and statistically significant effect on outcome (Children’s Depression Rating Scale-Revised change mean difference 9.12, p < 0.001), but actual treatment arm did not (1.53, p = 0.489).”

The researchers conclude that unblinding, which amplifies the placebo effect, may be the reason antidepressants typically beat placebo by a slight margin in clinical trials. They add that future studies need to make sure to assess unblinding in order to provide accurate data on drug efficacy.

“Our analysis suggests that the effects that are demonstrated in placebo-controlled trials of antidepressants may represent amplified placebo effects that are a result of the differential distribution of expectancy effects caused by unblinding. Since the expectancy effects are substantial, even a small degree of unblinding might produce an apparent difference between an active drug and a placebo. For future research, there is a clear need for more stringent study designs that systematically record and analyse treatment guesses and assess blindness, and do so early on and repeatedly,” they write.

Moreover, since clinical practice guidelines are based on evidence from studies like TADS, the researchers argue that guideline authors need to reassess the evidence base for their recommendations. Recommending antidepressants on the basis of studies like TADS is poor science.

Indeed, the evidence base for antidepressants—even for adults—is so poor that a recent article, authored by 30+ prominent figures in the field, recommends against their use in all but “the most severe depression.” The World Health Organization (WHO) guidelines agree: “Antidepressant medications are not needed for mild depression,” according to the WHO. There are plenty of other approaches, with fewer side effects, that are just as effective.

 

****

Jureidini, J., Moncrieff, J., Klau, J., Aboustate, N., & Raven, M. (2023). Treatment guesses in the Treatment for Adolescents with Depression Study: Accuracy, unblinding and influence on outcomes. Australian & New Zealand Journal of Psychiatry. Published online December 21, 2023. https://doi.org/10.1177/0004867423121862 (Full Text)

15 COMMENTS

  1. Prozac came on the market in 1988. How many lives lost or destroyed due to this long con? Because in my case, and many others, Prozac and its cousins served as gateway drugs to more serious MI diagnoses, more drugs (polypharmacy), labels like treatment resistant, non compliant, personality disordered, untreatable, led to other “interventions” like ECT…all while sucking up whatever resources the patient had while putting them on a fast track to disease, disability and death.

    The phrase “the absence of actual effect” could make someone think, “shrug, so it didn’t work. It didn’t cheer you up. So what.”. And not the reality: it ruined my life.

    I hate this society. I hate the FDA. I hate the mainstream media.

    Report comment

  2. I am gonna go all Loco with this one:

    What if actually this active placebo, fluoxetine, is the sham psychotherapy that should be used as a control for psychotherapy clinical trials?.

    I mean, fluoxetine is an active placebo in adolescents,right?, sort of, disregarding it’s harms. So either compare psychotherapy not to sham psychotherapy, but to drug placebo: a sugar pill.

    Or else, compare it with fluoxetine alone, an active placebo vs psychotherapy. And fluoxetine has no mechanism to improve depression, beyond active placebo, right?.

    Oh!, they already did that!. There is a CBT group alone!: “Fluoxetine alone is a superior treatment to CBT alone”, “Rates of response for … fluoxetine alone, 60.6%…CBT alone, 43.2% … and placebo, 34.8%”. From:

    https://pubmed.ncbi.nlm.nih.gov/15315995/

    Saddly, “Rates of response were … 86% for combination therapy, 81% for fluoxetine therapy, and 81% for CBT at week 36. Suicidal ideation decreased with treatment, but less so with fluoxetine therapy than with combination therapy or CBT. Suicidal events were more common in patients receiving fluoxetine therapy (14.7%) than combination therapy (8.4%) or CBT (6.3%). ”

    So, at 36 weeks CBT and the best “active placebo”, fluoxetine are no different. So, at 8 months, CBT is as effective as the best effective placebo, without as many suicidal events.

    From:

    https://pubmed.ncbi.nlm.nih.gov/17909125/

    Though, it does NOT report in the abstract the actual placebo rate. Hum,interesting…

    So, short term CBT is worse than the best placebo for major depressive disorder in adolescents, and loger term no different in MDD response. Hum, interesting…

    On another note, that to me speaks of the importance of having a theory to do interventional studies, not merely correlational:

    What if people who guessed correctly they were on fluoxetine were, for whatever reason, more likely to improve than the 40% that guessed wrong they were on fluoxetine, or the 50% that guessed wrong on the placebo?.

    At first look the placebo group might correct/control for that, but, what if it’s a double whammy: you will improve if you can guess, but, caveat, you actually have to guess correctly (your bet has to pay off with a feeling something cookie-pill): i.e. you need to be exposed to an active placebo?. And still requires the person’s ability to “feel” correctly the fluoxetine, even if, as stated will not improve depression per se.

    Or am I wrong?, does this study separate the “active” placebo from the “guessing” ability?. Sounds unparsimonious* to me, but optimism, confidence in the treatment might require, actually, the ability to “feel” something correctly during treatment, to be better than feel nothing placebo. So, the active placebo, stated thus DEPENDS on the ability to “feel” fluoxetine, even if it won’t do one no good depression wise.

    Supporting my crazy hypothesis, per the authors:

    “However, some authors point out that unblinding may occur because of therapeutic effects… though several studies across diverse conditions show that whether people guess they are taking active drug or placebo predicts clinical improvement INDEPENDENTLY OF THE EFFECTS OF THE DRUG…”, but saddly for my hypothesis does say that guessing you are on actual placebo leads to improvement. Maybe guessing ability works with actual placebo too?. Hahahaha, guessing ability was not tested directly, is there a theory for that?.

    *It sounds unparsimonious, i.e. not the simplest explanation, but considering the findings might be excusable, I think, when trying to put the paper in a single paragraph: Somehow, fluoxetine works because it’s not a placebo that works actually like a placebo because it is a placebo better than actual placebo.

    Or, it is a better placebo because it is not a placebo but it’s no treatment for MDD either, so in fact, it is a better placebo because of that: it is not a treatment and it’s different than other? placebos used in clinical trials.

    Like Schrodinger’s cat for placebos and treatments but it meows to the observer outside the box, so that 60% of the time, instead of 50%, the observer can guess the kitty will be alive, inside the box is both, dead and alive. So, maybe, theoretical physicists should give fluoxetine to the kitty in the thought experiment in Schrodinger’s cat?. Or, oh, oh, the experimenter should take fluoxetine to increase his/hers guessing ability?.

    🙂

    Seriously, psychotherapy instead of sham psychotherapy should use an active placebo, as a pill, that actually does not causes the HARMS that fluoxetine causes to SOME people, not all. So, effectively, fluoxetine for some might be an active placebo, for others is merely ineffective, the, uuuhh, dreaded and in vogue “treatment resistant depression”, for some is a nocebo/harmfull (it can cause mania/hypomania,akathisia, suicidality, etc.), or dang right fatal for some…

    Report comment

  3. “Since it was launched in early 1988, Prozac has been one of the biggest-selling drugs in history; its $21 billion in sales represents some 30% of Lilly’s revenues in that period. It’s not too much to say that Lilly is the house that Prozac built.Aug 13, 2001”

    From https://money.cnn.com/magazines/fortune/fortune_archive/2001/08/13/308077/#:~:text=Since%20it%20was%20launched%20in,the%20house%20that%20Prozac%20built.

    Pretty good for “no better than a placebo”. But a big downgrade from “miracle drug”, which is what the MSM was calling Prozac in the late 80s and early 90s (before links were made between prozac and homicidal and suicidal behavior)

    Report comment

  4. Prozac made me feel nothing rather than happy, so I didn’t like it, but this article is titled “antidepressants” when the only medication discussed is Prozac. It’s disingenuous and sensationalist to apply the study of one medication to make sweeping generalizations about an entire genre. And anyway, placebo study is nothing new. I hated Prozac and came up with some teen edgelord idea of being “my true self” rather than take medication, and was unhappy for about 10 years more than I needed to be when I finally started taking medications and found one that worked.

    Report comment

    • You need only type “SSRI” or “antidepressant” in the search bar of this website to find articles linking to studies showing that no treatment for depression has been shown to be better than a placebo.

      How is it disingenuous or sensationalist to finally report the truth about a drug that’s been on the market for 35 years? A drug that was hailed by the mainstream media as a “miracle”? That’s kind of a ridiculous statement considering that the “entire genre” of antidepressants were marketed and prescribed based on a “chemical imbalance theory” that’s been debunked several times over. “Placebo is nothing new”? Do you understand the point is that patients were lied to? Do you understand that that’s not okay?

      Report comment

    • This article uses “antidepressants” and “Prozac” interchangeably because Prozac is the only antidepressant that is FDA approved for treating depression in adolescents. That is, even proponents of antidepressants agree that Prozac is the only one that might have a positive effect in this population. However, as this study and others demonstrate, there is plenty of evidence that Prozac is just as ineffective and harmful as the other SSRIs for adolescents.

      Report comment

  5. Why does everyone who claims to be happy on psych drugs/claims that they “saved their life” sound so angry? Why do they have so much trouble when faced with the reality that psychiatry is pseudoscience? Why do they show an absolute lack of compassion for people who were harmed by the drugs and make efforts to silence psychiatric victims?

    It seems to me that if these people were really doing as well as they claim to be, they wouldn’t have such a hard time when they encounter information that challenges their beliefs.

    Report comment

    • That’s a good point, I think a genuinely happy folk would be unlikely? to realize that his/her comments might be innapropiate when presented evidence that what they see as beneficial for themselves is actually harmfull for most other people.

      Impulsivity and it’s correlate arreflexivity is a known side effect of antidepressants, without medicalizing nor pathologizing. But to me generates enough suspicion when presented empirical evidence their claim does not hold to experiments, if admitedly, in my view, unscientific. But more solid as claims than mere personal anecdote of benefit, not of harm.

      Even not so happy folks, even if claiming are happier now, like those “recovering” from substance abuse are more carefull when speaking of the times they felt great using “harmfull”, for some, substances. And legal on top of that.

      I was going to argue differently, and asking for literary license, what if gambling, streetfighting, dogfighting, and shoplifting were somehow “recognized” as happiness promoting treatments for “real depression”?.

      You know, as some quoted expert here at MIA, not just “sadness”, which an “expert” can easily tell appart, according to him, even if other research proves his expertise either fake or useless.

      Imagine self help groups founded by tall figures in the psy disciplines that have published some “scientific articles” claiming so?. Promoting those pernicious, but exhilaration inducing activities pandered that freely, without restaint nor resistance to the public?. Without prudence and self-awareness… without respect.

      Prescribed once a week, particularly on weekends?, for a comission and travel expenses covered to lecture those not yet prescribing it?.

      Wouldn’t we be reading comments of how great and life saving not yet “pathological gambling”, not yet disabled or incarcerated streefighting, not yet shamed dogfighting, or not yet incarcerated shoplifting are?.

      Even after decades devoted to them?.

      “Oh, it save my life!, you are overgeneralizing!, dogs are so corageous!”.

      Give me a break, self awareness, prudence, empathy, reflexivity and common sense is what comes from people who felt great using substances that in the long run, for some, caused great harm. After they realized how damaging were for them.

      But there are narratives and research, empirical, not scientific, that SSRIs and SNRIs not only cause lack of empathy, lack of “insight”, impulsivity, increased agression and sexual dysfunction for many. Among many others, those I think are among the top 5.

      Ignoring the derivatives of those increased/decreased behaviours: like what happens when one cannot enjoy anymore one’s sexuality?. Would that not be enraging and lashing inducing for some?.

      And respectfully, but given the recalcitrancy: the impairment of actually reading an empirical research review in the psy disciplines. But I have not seen that research published.

      What if that is one side effect not yet described of antidepressants: the inability to effectively understand empirical research on the psy disciplines. And confusing somehow my benefit with everyones harm?. Like a series of linked, or maybe not, cognitive biases, impervious even to in the best hands CBT?. And despite so clearly presented evidence… euphemistically, I asked for literary license.

      Would not the previous paragraph be a more parsimonious explanation for some comments?.

      But I have not seen published research on that.

      But to jive with the mood… in my disordered lived experience that might be the case. And it might be life saving if someone did carefull, up to the test, empirical research on that. Not understanding empirical research despite the evidence of real, actual harms, might be dangerous for some people. So, not understanding that might generate concern in even the most considerate and sympathetic folks.

      So my comment kinda has the tendency, despite its potentially inflammatory interpretation, to be for the common good. 😛

      Just a pun, I beg pro antidepressants folks, and yes moderators, to take it lightly, let’s be happier, with, or without antidepressants. After all joy, happiness and a sense of community is what, in part, we are seeking for, I guess, commenting at MIA?.

      Understanding and knowledge might or might not be a given though, for some reason, maybe or maybe not related to antidepressants use…

      But, despite my non use of antidepressants we can appreciate healthy sarcasm, hyperbole, euphemism and genuine concern for the common good?.

      🙂

      Report comment

  6. I knew I was getting the real thing because everyone kept wanting me to think about all the people I’d be helping. So it’s not like the trials (the ones I was in anyway) were blind studies, the doctors obviously knew who was getting which. Any time I reported adverse effects or feeling blank, I was reminded of the lives that could be improved.

    Report comment

  7. There is A trivial layperson answer for published research and testimonials of benefit of using antidepressants, that given the ignorance in the research, about how they work, cannot be controlled by current empirical psy research:

    What if antidepressants increase the likelihood of answering, true or not, fake or genuine, “I feel better”, or it’s superlative, “I feel great”, whenever asked: “how do you feel now?”. Like an answering inducing drug?, like a fake monotonous response serum?.

    Regardless how, why and how often, just increased likelihood, for whatever reason, to answer that even if not asked!?. Like a reflex, as Duran Duran sang…

    That some pundits of such empirical research might claim it’s a ridiculous critique*.

    Prove it is ridiculuous!, show me the body!, habeas corpus!.

    A simple 2 premises one conclusion might be convicing or at least discussion forwarding.

    Saying some critique is ridiculous or analogous statements don’t make it so.

    What if that is what is meassured?, a confounding variable that can’t be controlled precisely because no one knows, even top experts in the psys admit thus, how, if at all, antidepressants work, after decades and billions spent trying to invent how they “should” work. Literaly…

    And to try to weed out from the hip predictable, without much effort, anti-critique responses:

    It can be both, and my critique might be A stronger effect than whatever proposed…

    Like: it could be insulin for diabetes, it could regulate neurotransmiters, it could downregulate neuroreceptors, it coud “balance”, hum?, neural circuits, “we don’t know”, it could restore, hum?, circadian rhytms, AND it could induce, true, false or fakes: “I feel better”…

    🙂

    Cheers, let’s not take us so seriously, humbly…

    * Actually, that’s how in the lab research is actually evaluated BEFORE it is carried out. The researcher proposing an experiment must control for the easy to see confounding variable BEFORE doing the experiments. And that requires a THEORY of how and why the independent variable affects the dependent one. If the researcher cannot do that with such trivial to come up with confounding variable, that research, to my low scientific standards, is not worth doing.

    And psychiatry has no way to know what IS a confounding variable when it comes to how ANY psychiatric medication works.

    Report comment

  8. For me, the big takeaway is that you get no adverse effects with a placebo. Even if Prozac “works”, you are still subjecting yourself to a whole host of adverse effects and potentially, suicidal feelings. I remember feeling suicidal for a couple of years on antidepressants and Valium—-and I thought it was me. What an awful thing to do to anyone…..not to mention the flattening of affect (I had that too, which is what made me feel suicidal) and the awful effects on sexual response. Thank you, Peter. I can think of several people who may benefit from reading this article.

    Report comment

  9. My dentist and parents conspired to diagnose the family with a fluoride deficiency from an early age, and so we drank gallons of fluoridated water trucked in especially for us. At 19 I was offered fluoxetine and I couldn’t just say no. So my mother was overjoyed to “have me back”, but perhaps this brief glimmer of recovery was thanks to seeing a psychotherapist who was sympathetic, charismatic, and optimistic rather than the pills I detested. After that it was just drugs, drugs, and drugs. Medicaid doesn’t really care about efficacy.

    Report comment

LEAVE A REPLY