Are Antidepressants Better Than Placebo for Some? Not So Fast, Researchers Caution

Researchers argue that the recent study finding antidepressants beat placebo for about 15% of people doesn’t account for study unblinding and includes only extremely short-term data.

8
1921

In a recent BMJ article, researchers found that antidepressants may be better than placebo for about 15% of people. While this means that 85% of those on the drugs are exposed to the harmful effects (commonly including weight gain, sexual dysfunction, and emotional numbing) and withdrawal effects of the drugs without benefit, it could still be considered a positive finding. At least there is some group of people for whom the drugs seem to be beneficial.

But according to other researchers, even this conclusion is too optimistic. In two “rapid responses” that also appeared in the BMJ, researchers suggest that this positive finding may be due to unblinding in the studies.

Retired physician John Warren puts it succinctly: “The small additional fall in [depression symptoms] with active treatment is consistent with the effect of using an active placebo, where experiencing side effects from active treatment adds to the belief in efficacy.”

The researchers also caution that this data comes from short-term studies, usually about six weeks long, and that long-term randomized controlled trials simply don’t exist. Thus, it is unclear if the drugs are safe or effective—for anybody—over the long term.

According to Warren, “It is a major concern that the most frequent duration of the trials was six weeks and we have no data beyond 12 weeks. These drugs are frequently given for years and this is not consistent with international requirements for other areas of long term therapeutics. The lack of proof of long term efficacy is important, the lack of long term safety data even more so.”

A pill bottle with a question mark on its label in front of other bottles.

In the other rapid response, researchers Mark Horowitz, Florian Naudet, Janus Jakobsen, Martin Plöderl, and Joanna Moncrieff agree that study unblinding is likely the cause of the slightly larger group who benefit from the drugs.

“Unblinding by side effects… might amplify this effect for the drug group,” they write.

They add that the post-hoc statistical analysis used in the original paper may not be appropriate. They write that this type of analysis should be considered exploratory and is not comparable to prespecified outcomes in a well-conducted trial. It also doesn’t provide any information about how to identify the supposed 15% of people who benefit, because it is dependent on every patient having a higher or lower probability of being in that group—not identifying the specific people in that group.

“It is not clear that focusing on change from baseline scores in undefinable sub-populations of patients is informative. As these are theoretical distributions, each participant has a probability of belonging to each distribution so that the technique does not identify a group of people who show a “large” response or one that benefits more from antidepressants,” they write.

They note that the less controversial result of the study is that, on average, the researchers found a 1.75-point difference (on a 52-point scale) between the antidepressant and placebo—a clinically insignificant result that neither patients nor their clinicians can detect.

The original study included only clinical trials, which hand-pick their participants, searching for those with no other conditions and who are not suicidal. This makes them very different from the individuals most often treated with the drugs in real life.

Other researchers this year found that response to treatment is low in real life. In a study where over a thousand people with depression were treated with antidepressant drugs—more than half on multiple drugs—as well as therapy and hospitalization, less than a quarter responded to treatment.

In another paper, those same researchers also found that those with more severe depression, those with comorbid anxiety, and those who were suicidal were least likely to benefit from the drugs.

And other researchers have repeatedly found that in the long-term, those who take antidepressants end up feeling worse than those who don’t—even after controlling for baseline severity and other factors. Researchers argue that use of antidepressants leads to a more chronic, recurring depression, while those who recover without using the drugs tend to return to normal functioning.

 

****

Warren, J. B. (2022). Re: Response to acute monotherapy for major depressive disorder in randomized, placebo controlled trials submitted to the US Food and Drug Administration: individual participant data analysis. BMJ, 378, e067606. https://doi.org/10.1136/bmj-2021-067606 (Full text)

Horowitz, M. A., Naudet, F., Jakobsen, F., Plöderl, M., & Moncrieff, J. (2022). Data modelling in search of meaning. BMJ, 378, e067606. https://doi.org/10.1136/bmj-2021-067606 (Full text)

8 COMMENTS

  1. Prozac gave me huge dilated pupils, but so does Belladonna. A poison.

    I am curious as to why so many people have gone on to these drugs given all the reports of how awful they are. Are people that stupid or is something else going on. I would suggest that there has been a cultural change in the way people are no longer quite so afraid to admit that they are depressed. It could be similar to social contageon. Maybe looking bright and breezy is the new stigma. I remember my pill popping pals were always feeling their depression was validated “if” they came home with new special blister packs. At that time I thought their motive ran along the lines of….

    “I am only worthy of care IF I am seen to be suffering from the deepest depression, far worse than any depression that ever went before it”.

    I thought that was appalling. All beings are worthy of care even for being healthy. Dogs and cats get cuddled for being healthy.

  2. You know what? There is a question I want to ask. And that is, why are double blind studies like this regarded as “the best” or regarded as “the gold standard?” Or, regarded as “the only way” to figure out whether something is good or not?

    I just think the world is not that simple, and sometimes alternative methods should be tried.

    I think anecdotal examples should be taken seriously, and investigated. We have enormous genetic diversity and many different sub populations. Depression may not even be all one disease but the symptoms of several different diseases or problems. Which could explain why some respond to SSRI’s and others don’t.

    Wouldn’t it be nice to try to investigate what the underlying cause is, if not a chemical imbalance? See the declaration of a “chemical imbalance” was almost done in order to forestall additional research like that, which would make the blockbuster prozac look bad. Or reduce the number of people prescribed it, reduce the customer base.

    In particular, EVEN WHEN SSRI’s help symptoms, they may be a bandaid. For instance, like prescribing morphine for a muscle imbalance causing pain without fixing the muscle imbalance.

    What I hate is this conservative philosophy involving everyone jumping on the bandwagon of a fake “explanation,” but the purpose is to cut off scientific debate, which also amounts to cutting off or preventing areas of research which people who are inspired, creative, idealistic, etc., would love to do because they love science and exploration for its own sake, and not even for money’s sake.

    Indeed, it strikes me that there is this cultural problem whereby those who care about money will always exclude or ostracize from academia those who are too idealistic and who will chaff at such reigns being put on them solely for the sake of money.

    I ought to note, this is very important because I once spoke to a gay man I hooked up with who was in biotech about the whole issue of corruption in medicine. He said medicine is very corrupt.

    And, right off the bat, he told me that perhaps the biggest area of corruption there was with pharmaceuticals was tied to the failure to recognize genetic diversity and the failure to identify and study different sub populations, and design drugs that are tailored specifically towards them.

    Pharmaceutical companies insist on the “blockbuster” drug model, where they can find one drug they are able to market to the whole entire population, and they would never make as much money if they studied genetic diversity and assumed that a drug that worked for one person won’t work for another, so they have to tailor each drug for each sub population.

    The R&D costs as a ratio of the final profits simply would be too high if they did that.

    And this problem is endemic to ALL of medicine. Not just psychiatry. Though this man also said that, while all of medicine is corrupt, psychiatry is the most corrupt. “If you have enough money, you can buy ANY research result you want in psychiatry.”

    Another interesting side point is, Identity Politics has made it politically incorrect to even study either gendered brain differences or race/ethnicity brain differences. Currently, the cultural conversation would say that further studies shouldn’t be done because the results would be insulting to minorities, but I am not so sure that would be true.

    I personally know that, when I was at Harvard, they had this teaching style in math that was just terrible for me but good for other students, and they hinted to me that they knew I was different in a way that didn’t make me less smart at math (maybe I was more smart at math than the average Harvard math student), but that I was still at a disadvantage anyway because of their style which was “how we HAVE to do it, because this is America.” And they even explained, I should have gone to college in Europe because, if I went to a place like Oxford, they have the more sociable learning style with the kind of mentorship I need for my mind to fully engage.

    They didn’t make any smoking gun statements but their beating around the bush suggested guilt of some sort. Many years later, my inevitable conclusion is that Harvard and other colleges in America have deliberately figured out a learning style or teaching style or tradition that is best suited towards upper middle class anglo saxon protestant WASP types, as well as those whose families gave them the best preparation, and is deliberately meant to disadvantage blacks, Italians, some Jews, and other types of more “ethnic” people who tend to have stronger family traditions and are in need of more “sociable” learning styles and are less cold. And who are more likely to be athletic and who are also stronger at the geometrical side of math, even while the Harvard Math Department tends to have a bias towards algebraic types of mathematicians.

    And I believe places like Harvard have done research which they never divulged that helped them figure out how to engage in teaching styles meant to advantage America’s elite whites above both black and other ethnic immigrants.

    I strongly believe the few studies that were done on race brain differences were artificially rigged so as to make certain minorities look inferior, all the while I suspect lots of “underground” studies have been done designed to develop teaching styles that artificially privilege Establishment American Whites, all so as to make the rigged studies suggesting inferiority of other groups become self-fulfilling prophecies.

    America IS White Supremacist, and it is not a few blue collar troll like men in the deep south or other red state areas of the country who are the primary white supremacists. It’s the establishment that is, including the liberal establishment.

    I also note health outcomes in America are VERY poor for blacks — and these disparities are VERY profitable for pharmaceutical companies. Knowing what I know about Harvard now, I believe Harvard and similar institutions may well have done underground studies which they covered up using the mafia that may focused on race secretly, and they may have figured out why health outcomes are poorer for minorities, only to cover up the research, deny such groups the knowledge they need to have to achieve better outcomes, and even gone further and tried to promote all the wrong things they knew would guarantee the bad outcomes so profitable to their corporate donors.

    I just wonder, though. Do you think Identity Politics in and of itself — which was a creation of academia and of our cultural elite — do you think that might be a forces which is helping to give academia an excuse to avoid study of sub populations and genetic diversity, so as to prop up the blockbuster “one size fits all” drug model most convenient to Big Pharma?

    I think it might be. And I say this in large part due to having lived for awhile in Dorchester in a black area myself, and learned of some of the appalling things that go on, which are none other than systemic racism practiced by the most ardent adherents to Identity Politics. And which include doing unethical involuntary medical experiments on poor blacks from the inner city, which are no different from how Hitler experimented on the Jews in Auschwitz. So, I mean, come on. Those trumpeting Identity Politics aren’t doing it for the minorities themselves. So who else might they pushing Identity Politics for? Maybe the corporations with the money?

    Take, for instance, the black-white schizophrenia diagnosis gap. Victims of unethical medical experiments perpetrated by the mafia usually do end up getting diagnosed fraudulently with schizophrenia to cover up the crimes. So that, in and of itself, might be a good explanation for the wildly divergent rates of schizophrenia diagnoses. E.g., certain black neighborhoods are laboratories for unethical medical experiments, but absent being honest about it and putting them in concentration camps, complex criminal racketeering schemes involving a fraudulently imposed diagnosis of schizophrenia suffice instead.

  3. How many people are you willing to sacrifice to real anti-depressants? And why do you think anyone would ingest placebos, thinking that they are real?

    Why do you think anyone would cooperate with any of this at all. Wouldn’t the cooperation rate be the most telling statistic.
    If it is more than 2%, then something is seriously wrong. Doing stuff like this on captives or with deception is completely illegal.

    Joshua

    • Do you know that infrared light, shone on the skin, will increase serotonin?

      Here, let me post this link:

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4935255/

      And then this:

      https://saunas.org/infrared-therapy-for-depression/

      “Several biochemical changes occur in the body as a result of exposure to near, mid, and far-infrared light. The triad effect of increased release of dopamine (a neurotransmitter), beta-endorphins (a neuropeptide hormone), and serotonin (the precursor to melatonin) during and after an infrared sauna therapy sessions may raise as well as stabilize mood (4).

      This cascade of pleasure hormones released in response to the infrared light wavelengths makes this particular healing modality an excellent choice for individuals suffering from depression.”

      —-

      Now here is the thing. I have a cold laser and have tried using it to treat my head trauma symptoms. And I’ve used infrared heating pads in the past. I feel like I don’t like the infrared heating pad because, while it definitely will cause a temporary high, my brain adjusts to it. Plus, I don’t want to be dependent on it.

      However, I DO like outdoor exercise. Which is known to cause permanent improvement, including building more brain tissue. Stimulating the growth of more brain tissue.

      I believe that, when you exercise outdoors, you get the infrared light rays from the sun shining on in and into your head, which you don’t get indoors. And newer buildings are worse than older buildings in terms of what light rays they block in order to be energy efficient. At the same time, you get various olfactory stimulation outdoors you don’t get indoors — again, newer buildings really bad in this regard.

      But, somehow, I think the outdoor exercise does more than mere symptom treatment but actually reprograms the brain somehow. E.g., you are getting the light rays and olfactory stimulation at the same time as your muscles are working and producing various chemicals on their own — which, I think, somehow tell the brain to get better.

      And I think it’s a mechanism where you need all three conditions — outdoor olfactory plus infrared plus exercise — in order for it to work. Can’t have a missing piece of the puzzle, you know.

      Anyway, I would suspect the people who benefit from SSRI’s probably would also benefit from infrared light therapy as well. Except that’s artificial. They’d probably benefit from the right type of outdoor exercise.

      Oh, you know, it never occurred to me before but I’m realizing it now. Little kids with ADHD might also be having issues with modern buildings that block certain light rays their brains need in order to grow right. Something like that.

      Oh, look at this. Skull thickness really makes a difference as to light rays penetrating your head and stimulating your brain.

      https://pubmed.ncbi.nlm.nih.gov/1224277/

      Notice white women do get depression lots.

      Also, I should explain, infrared light hitting the SKIN causes a reaction that produces serotonin and a few other chemicals, I think. However, infrared light also penetrates the skull and directly stimulates the brain as well. Meaning, there are two mechanisms for stimulation of red light.

      Hmmmm, you know one could speculate that lower levels of depression in black people could even be because black skin absorbs light that much better than white skin, isn’t that interesting?

      See, here’s the thing. SSRI’s seeming to help some people but not others should have been regarded as a clue to what might be going on with depression, that should have called for more research identifying a mechanism that might result in better treatment.

  4. I am not a maths genius or an expert in experimental design but if the overall benefit of antidepressants is slightly better than placebo (but not to a clinically significant degree) but 16% show a much bigger improvement then by reason are there not a similar proportion of people significantly harmed? Would that not have to be the case to balance out the figure? If so does this not need investigating to find the true risks and benefits if these drugs?

    • You are right, of course. If 16% are significantly helped and the overall benefit is barely noticeable, there must be a significant number who are harmed to balance out that 16%. That number rarely seems of interest to psychiatry. They don’t seem to be interested in finding out who the 16% are who DO benefit from these drugs and letting the rest look for other help. It would destroy their and the drug companies’ bottom line.

      • Do you know what is especially ….. I don’t even know what to say or how to say it ….. especially mind numbing about this?

        This is sooooooooo bad, what they are doing here, it is so bad, it is shocking to the point of being unbelievable.

        At the same time it is this bad, drug companies have managed to rope all sorts of institutions of higher learning into schemes this bad, all of whom work so hard to develop this aura of properness and respectability, complete with all sorts of authoritative jargon and very dignified sounding speech.

        Even to the point where Harvard itself is complicit in this too.

        Indeed, I remember when I was being victimized by the mafia in connection with Harvard, for awhile I spoke with this Malena person, who was Russian Jewish and told me she knew many holocaust survivors. She told me that my situation reminded me of a story she heard regarding a concentration camp inmate who scaled the barbed wire fence and tried to escape. And, normally, the guards would have shot him, but in this case, they spared his life, and also proceeded to explain to him: “why are you even trying to escape here? Don’t you understand, the things that go on here are so unbelievable and so far beyond the realm of human comprehension that, if you escape and try to tell anyone what goes on here, they simply will not believe you but will think that you are crazy.”

        I think drug companies have the same thing going on with their bribery of doctors and institutions of higher learning. It’s outright criminal, what is going on, and they should be criminally prosecuted for this. Even worse, ALL OF THEM are doing it, so many that, in order to crack down on this, you’d literally have to expand the prison system in order to house all the co-conspirators.

        But then, they are doing it all in plain sight, not even trying to cover it up, and trying to rely instead on bluff, an arrogant kind of bluff. If anyone questions them, they will act outraged and be like “I’m a [insert title and qualifications] how dare you question me?” Which is nothing but outright intimidation.

        People just want to be enablers and just want to believe. It is sort of like wanting to believe in the good and wanting to think positively. You don’t want to believe that many people could be this bad and lie through their teeth this badly, so you choose instead to believe they are probably mostly doing the right thing.

        That’s a mistake. It is necessary to be that cynical. Sort of like how you have to fight fire with fire.

        Oh, even worse, it is necessary to be so cynical and such a “conspiracy theorist” that the very definition of schizophrenia begins to loom as a potential source of fear. You have to harbor a kind of distrust of the psychiatric profession that would give them the perfect opportunity to diagnose you schizophrenic or at least “paranoid.”

        Except, actually, it’s HEALTHY to be that skeptical and not healthy to blindly trust OTHERS about your own health. Part of recovering from various health issues is listening to your own body, trusting yourself, and — it is almost as if you are the one in charge of your own health and you are the one who knows the best regarding your own health. Including or especially mental health. And the ability to “mind over matter” heal oneself has been underestimated by the medical profession.

        Remember, health outcomes are way better in Europe than the United States, and they have government provided healthcare, and you know what the government is like. I once was hospitalized in Quebec so I kind of know. Everyone says the private market does way better than the government at catering to the consumer, and that is true. Health is an area where you do better when you are catered to much less. And what those government health agencies are telling European populations, with their rationing and long waits is: “you are on your own.”

        That, in and of itself, might be responsible for much of improved European health outcomes. I am reminded of how victims of PTSD induced “dissociative disorder” need to “pull their brains together” in response to the trauma, and I note it’s been said that anti-psychotics hinder rather than help that.

        Well, even if you don’t have PTSD, I think somehow the same principle might hold true with respect to your health. Europeans know they are on their own, and that makes them more attentive to their health in ways Americans are not, because Americans are coddled too much by consumer culture.

        I think our whole entire culture might somehow impact that kind of thing too. And we in the USA are not even aware of it because we are too used to it.

        The truth is, we are an empire similar to how Ancient Rome was an empire. And lead poisoning was a favorite for them.

        Also, in contrast to America, Europe is a much older country and Europeans still cling to traditions more — which can have its downside, but also has its upside. And Europeans resisted jumping on the psychiatric bandwagon far longer than America did.

        See, in America, you can have someone be the “big man” and do a bunch of smoke and mirrors “authoritarianism” sounding tricks, and it works. People here get brainwashed. Not so much in countries that are older and held onto tradition more.

        I suddenly am reminded of Obama saying those who vote against him are ones who’d “cling to guns and religion.” Which is rather insulting. Actually, even with religion and guns, it’s as if America does traditionalism in the same wrong-headed way too. The problems of American culture EVEN INFECT those who would want to “cling to tradition more” in a healthy way, so it just becomes like another version of all the same wrong-headed stuff in psychiatry.

LEAVE A REPLY