Antidepressants’ Superiority to Placebo in Major Depression Challenged By Reanalysis


The October edition of the Journal of World Psychiatry, the 3rd ranked journal of Psychiatry, will publish a reanalysis of antidepressant efficacy versus placebo in major depression.  When the researchers, Arif Khan and Walter Brown, analyzed the data from the FDA archives for antidepressants approved between 1985 and 1997, “it was evident that the conventional wisdom of 70% response with antidepressants was at best an overestimate.”  In fact, “the magnitude of symptom reduction was about 40% with antidepressants,” compared to “about 30% with placebo.”

“It quickly became apparent that many of the assumptions about the relative potency of antidepressants compared to placebo were not based on data from the contemporary trials but from an earlier era,” they wrote.

The researchers also compared clinical trial data about antidepressant effectiveness in major depression from non-pharmaceutical industry funded sources and industry trials submitted to the FDA. They did not, however, account for financial conflicts of interest among the authors of the “non-pharmaceutical industry” trials.

Nonetheless, the magnitude of symptom reduction for those in the placebo group was found to be higher in the “non-industry” trials.  This is an important finding as a lower response to placebo in critical registration trials could inflate the drugs perceived efficacy.

When the researchers examined the difference in study designs between “non-industry” trials, they made another interesting discovery.  In trials where the investigators and their staff were aware of the plan and the expectations of the study, the magnitude of symptom reduction “followed the pattern of accepted expectations.”

“Clearly, investigator and rater bias influences the magnitude of symptom reduction with all treatments, whether they are approved treatments, active controls, passive controls, sham treatments, treatment as usual, waiting list, or placebo,” they wrote.

When investigators remained “blinded” to the design and expectations of the study, however, “the symptom reduction with each treatment was of smaller magnitude and the differences among the various treatments and controls were also smaller.”  In fact, under these circumstances, the depressed patients, no matter what treatment group they were in, reported symptom reductions that were not significantly different from placebo.

“In other words, when the level of blinding was high, and it was difficult for the investigators, their staff and depressed patients to guess treatment assignment, the differences between these treatments, controls, and placebo became quite small.”

The researchers conclude: “The effect size of current antidepressant trials that include patients with major depressive episode is approximately 0.30 (modest), and this fact needs to be heeded for future antidepressant trials.”

In a commentary to appear in the same journal, MIA author Joanna Moncrieff challenges that there are “no grounds to believe” that these drugs “have specific effects that would justify their classification as ‘antidepressants’.”  She points out that the sedative effects of these drugs on their own are likely to have an impact on depression scales.  For example, “changes in sleep alone can account for up to 6 points on the Hamilton Rating Scale for Depression.”  But that does not necessarily mean that the drugs specifically target the symptoms of depression.

She also notes that the effects of the drugs can alert the research subjects that they are in an active treatment group, which “may create or exaggerate a difference between antidepressants and placebo.” “Unless the psychoactive effects of antidepressants are somehow discounted,” she writes, “differences between antidepressants and placebo cannot be interpreted as providing evidence that those drugs have a specific ‘antidepressant’ effect.”

Moncrieff concludes: “We need to recognize that antidepressants are psychoactive substances, we need more data on the nature of the varied psychoactive effects they produce, and we need to explore whether giving drugs that produce an artificially altered emotional state is a useful and acceptable intervention for people with depression.”



Khan, A., & Brown, W. A. (2015). Antidepressants versus placebo in major depression: an overview. World Psychiatry14(3), 294-300. (Abstract)

Moncrieff, J. (2015). Antidepressants: misnamed and misrepresented. World Psychiatry14(3), 302-303. (Abstract)



  1. This totally reflects Irving Kirsch’s work. A 10% difference between placebo and active treatment is essentially zero when you take into account unblinding by side effects. If we used active placebos, it is likely we’d see no difference whatsoever.

    Taking side effects into account, it seems that active placebos would be the preferred “treatment.”

    —- Steve

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    • I think you are exactly right, Kirsch’s work was right on the money. We know active placebos are more effective than passive ones. I wonder what would happen if an “overactive” placebo were used, i.e., one that had stronger side effects than the drug itself. Or if the patient were deceived (for the purposes of the study) and told he/she was getting the drug when it was actually an active placebo. Hard to believe all this has not been hashed out already…kind of basic to good science.

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    • Plus kicking out studies with conflicts of interest would likely do the same.
      Maybe we should stop calling these drugs “anti-depressants”. The same way we should not call crystal meth an anti-obesity drug (though this one can actually be effective for what it’s worth).

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    • LOL

      I just scrolled to the prize piece:

      “Moncrieff concludes: “We need to recognize that antidepressants are psychoactive substances, we need more data on the nature of the varied psychoactive effects they produce, and we need to explore whether giving drugs that produce an artificially altered emotional state is a useful and acceptable intervention for people with depression.””

      Has all of that not been said, consistently, countless times, for years? Hasn’t it been answered?

      “whether giving drugs that produce an artificially altered emotional state is a …. ”

      OMG, STOP.

      Isn’t that question (indicating a LACK of knowing and understanding) already answered?! Isn’t the answer NO?

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  2. Just for the heck of it, I’m going to post this yet again:

    “Major depression” is not a valid, reliable illness. The reliability ratings for major depression in the DSM 5 field trials were close to 0 (0.2-0.3). That means that whether or not one gets labeled with depression or some other “illness” is usually arbitrary.

    Feelings of depression of varying degrees can be caused by a multitude of different internal and external causes, and the combination of causes in each case is unique to the individual’s situation.

    Therefore these studies of “major depression” should be viewed with extreme skepticism.

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  3. The lack of efficacy of psychiatric drugs has always been clinically evident. The same is true for simplistic manualized psychotherapies. Now in addition to the study reported in MIA showing CBT is losing it;s effectiveness, there is another study indicating that manualized psychotherapy research has been tainted by the same publishing bias found in anti-depressant trials (
    The psychiatric industry has been plagued by the push for so-called evidence based treatments that has ended up supporting obviously inadequate and often damaging treatments.
    People are not paint-by-number kits. Real people need expert therapists who will treat them as individuals and work with them in a humanistic manner to deal with real emotional issues.
    For many years now, expert therapists have been thinking “WTF” in seeing ridiculous forms of superficial therapy promoted and expert complex therapies being devalued. It’s time to reject all the bunk and put our efforts to finding ways to really help those in need.

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    • “For many years now, expert therapists have been thinking “WTF” in seeing ridiculous forms of superficial therapy promoted and expert complex therapies being devalued.”

      That’s because we’re subjugated to the belief that the sufferer / individual has a biological disease. We’re form-fitted with psychiatric head cages (the diagnoses, the waste-of-time therapies, the service plans, the drugs) and made to endure brainwash and indoctrination. Some people even become self-made scholars, as they have to be, in order to defend themselves.

      Our personal problems and issues, and even our very self, can be pushed out of the equation. We then have the biggest problem we ever had and never wanted: becoming consumed by an industry.

      It’s almost like there are a lot of people trapped in the belly of an insatiable monster that needs people to feed itself, stay alive, and exist.

      I wonder how many people got an education they didn’t need, didn’t want, didn’t choose and didn’t go looking for. People just wanted support and assistance with some issues in their lives. They didn’t exactly want to become wards of the state, social activists, protesters, survivors, slaves…

      Lots of people are stuck in the “fix the system” camp.

      From your link,

      “Major depression is a highly prevalent and disabling disorder associated with major personal and societal costs [3–5]. It is the fourth leading cause of disease burden worldwide and is expected to rank first in high-income countries by the year 2030 [6]. Antidepressant medication is recommended as a first-line treatment for major depressive disorder in most treatment guidelines [7–8] and the majority of depressed patients are now so treated in primary care”

      My mind stops when I get to the word “disorder”.

      Isn’t it true that we’re born into a harrowing world? Isn’t it true that humanity is deceptive, and we go through disillusionment, and other such flattening true blue lessons of what it is to be a human being on planet earth?

      I looked up “disillusionment”

      everything tastes of porridge

      An expression used to inject a note of reality into our daydreams. The point is that no matter how grandiose our schemes or how successful our self-delusions, the taste of porridge or the reality of our domestic affairs will always be there to impinge on our fantasies. Porridge, formerly a staple in every household, is a most appropriate symbol of the practical, basic nature of home life.

      This is from Of Human Bondage, by W. Somerset Maugham

      “He did not know how wide a country, arid and precipitous, must be crossed before the traveller through life comes to an acceptance of reality. It is an illusion that youth is happy, an illusion of those who have lost it; but the young know they are wretched, for they are full of the truthless ideals which have been instilled into them, and each time they come in contact with the real they are bruised and wounded. It looks as if they were victims of a conspiracy; for the books they read, ideal by the necessity of selection, and the conversation of their elders, who look back upon the past through a rosy haze of forgetfulness, prepare them for an unreal life. They must discover for themselves that all they have read and all they have been told are lies, lies, lies; and each discovery is another nail driven into the body on the cross of life. The strange thing is that each one who has gone through that bitter disillusionment adds to it in his turn, unconsciously, by the power within him which is stronger than himself.”

      What if the “fourth leading cause of disease burden worldwide” is a harrowing state of heaviness from disillusionment (for at least some portion of those people)? If that were true, then it’s not a brain disease. It’s an existential condition (intrinsic).

      Am I seriously supposed to believe that the fourth leading cause of disease burden is depression, and that depression is entirely biological? What percentage of that massive group of people define their experience of depression differently from a biological disease? And where is the disease, anyway? In the brain? And there’s plenty of brain scans that prove which part of the brain is diseased? What else does that diseased part of the brain cause in its victims? Restless legs? Allergies? Inflammation? Digestive disease? Heart murmurs? Morbid attraction to The Darkness?

      I see a need for evolution of understanding. I seriously, seriously doubt that the fourth leading cause of disease burden worldwide is brain disease. A brain disease called depression.

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      • Right. Serious individual life problems and developmental/relational deficits do not constitute a “disease” or “disorder.”

        The practice of diagnosing and medicating is like a voracious profit-producing beast that needs new, uneducated, poor (financially poor) victims to keep maintaining its profit and power.

        That’s why educating people is so important so that they can have a chance to avoid or extricate themselves from the maw of the psychiatric leviathan (haha I must sound some sort of evangelical preacher speaking about the devil. But then again, “salvation” would be a better term for what suffering people need than “treatment (for brain disease)”.

        If many small individuals take action and try to educate others about the fallacy of the diagnosing/medicating approach to life problems, I think there is hope. It only takes a relatively small group to make a big impact. More people must become self-aware and opt out of psychiatry’s poisoned offerings in order for real change to the system.

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        • It also serves a political purpose: medicalizing suffering allows the privileged in society to continue to believe that they are better than the masses and that any objection or upset with their “benign” rule is due to failure in the person who is upset, rather than a flaw in the system that allows them to rule and look down on those they consider to be “the rabble.” It further allows those who are directly or indirectly expressing their dismay to be numbed into quiescence so that they will never be able to join forces and undermine the control of the privileged class.

          — Steve

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    • Good comment Norman. It never made sense that manualized treatments could be studied objectively. Even they are not like pills: Each therapist will apply them differently, and each client will require a different application even though the approach is supposedly uniform.

      A good example is DBT for Borderline PD. It can be damaging in various ways but the worst is that it explicitly frames BPD as a biological disease with possible genetic basis that the therapy is helping the person to “manage”. That framing is a disgusting lie.

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      • And given the individual nature of these “issues,” it is also ridiculous to think you can have some objective outcome measure, since each person has different objectives and values that inform both their use and their evaluation of the services offered. “Evidence-based” therapy is tainted from the beginning in that their “evidence” is based on the same assumptions as “treatment” with drugs: namely, that “symptom reduction” is the ultimate goal and that the client’s assessment of the goals and success of therapy is, at best, a secondary consideration, if it is even considered at all.

        You can’t create an evidence base without an objective way to determine who belongs in a particular group and what a “successful outcome” looks like. Psychiatry and psychology have both consistently failed to provide either, and have used their “checklist method” to cover for the fact that they don’t even know if their “treatment group” is a legitimate study group with a common variable to evaluate, let alone whether those so “treated” have made any measurable progress, since we really have no agreement or means of establishing what “progress” even means.

        The only appropriate measure of whether therapy “works” is whether the person receiving it says that it works, and that will never be a scientifically measurable outcome. Different approaches work for different people. There is no cookie-cutter way to do it, and efforts to provide one only create confusion. Which, no doubt, is the real purpose of “evidence based” therapy evaluations.

        —- Steve

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        • I agree with this thinking Steve.

          If you have not read it, I think Barry Duncan (The Heart and Soul of Change, the Heroic Client, books) does a good job of mixing the qualitative and quantitative approaches to measuring effectiveness of psychotherapeutic relationships. He always makes the point that it’s the perception of the quality of the therapeutic relationship by the client that matters most. Where is that in these studies?

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  4. I agree with your comments about DBT. It is also another form of therapy that has been overly promoted and manualized. While your comments about how DBT frames BPD are true, it is probable that DBT as it was done by Linehan’s group was helpful as it provides a lot of support for both patients and therapists and a lot of consistency and empathy. I’ve never believed, ( as is probably true of most therapies) that it has been specific techniques of DBT that may be most helpful. However, many centres are taking the techniques, dropping the holding and humanistic aspects, and marketing the resulting therapy. This seems ridiculous to me.

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    • Hi Norman,
      Thanks for your comment. I have read a lot about it. Sometimes it is applied as a way to help people cope constructively with problems without medicalizing them or without even speaking about diagnoses. Then I think it’s good. Otherwise, not so good as in the example I mentioned where it’s specifically linked to “managing your personality disorder.”

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