A Dangerous Truth about Antidepressants

By Neuroskeptic | November 25, 2011 9:25 am

An opinion piece by veteran psychiatrist and antidepressant drug researcher Sheldon Preskorn contains a remarkable historical note –

“A dangerous idea!” That was the response after a presentation I gave to a small group of academic leaders with an interest in psychopharmacology [over 15 years ago].

What evoked such a response? The acknowledgment that most currently available antidepressants specifically treat only one out of four patients with major depression based on the bulk of clinical trials data.

There was no argument about the accuracy of this statement, but…some claim it is “dangerous” to admit that the specific response rate to most antidepressants is 20%–30% because such an acknowledgment might undermine the value of antidepressant treatment.

By the “specific” response rate Preskorn means the number of depressed people who’ll get better on antidepressants and who wouldn’t have done so well on placebo. This rate is fairly low because, while most people get better on antidepressants, most of those improve on placebo as well.

Preskorn rejects the view that it’s dangerous to acknowledge this:

…there are several problems with this reaction. First, it is hard to deny reality. The “placebo” response rate in antidepressant trials is arguably the most reproducible finding in psychiatry. Moreover, if available antidepressants were magic bullets, then polypharmacy would not be so common. Second, this reaction ignores the fact that antidepressants are tremendously valuable to the patients who specifically benefit from them…

Every treatment in every area of medicine has limitations. Acknowledging that fact should galvanize us to action. Denial on the other hand perpetuates the status quo.

Unfortunately, we’re not told who these academic leaders were. I wonder if they included amongst their ranks some of the “key opinion leaders” in the field whose leadership proved rather less than ideal. The column is actually adapted from a 1996 article by Preskorn.

Preskorn is right, of course, that denying the fact that antidepressants are only substantially better than placebo in a fraction of people who get diagnosed with “depression” is wrong, and also misses the point: because hundreds of millions of Americans have diagnosable depression (due to the loose definition of “depression”), even if they only helped 1% of them, they’d still help over a million people.

But he doesn’t mention that this approach was ultimately self-defeating. As a result of the failure to acknowledge that antidepressants are only helpful in some cases of depression (namely “severe” depression), these drugs became very widely used and – oh dear – people started saying that the drugs are being overused, and don’t work in most people who take them.

Whoever could have seen that coming.

This has “devalued” antidepressants – and psychiatry itself – more than anything else has.

ResearchBlogging.orgPreskorn SH (2011). What Do the Terms “Drug-Specific Response/Remission Rate” and “Placebo” Really Mean? Journal of psychiatric practice, 17 (6), 420-424 PMID: 22108399

  • Michael Browning


    Interesting post. It's possible that severity is not the only aspect of depression which predicts antidepressant efficacy. For example, the effect size of antidepressants in dysthmia (milder symptoms of depression, but more chronic course than major depressive disorder) seems to be greater than in MDD (Levkovitz et al. 2011, J Clin Pysch 72(4)). This is secondary research, with all the associated caveats, but suggested that the improved efficacy was due to a lower placebo response in the dysthmic studies which seems reasonable.

    Anyway, it suggests that antidepressants may be useful in milder, chronic forms of depression.


  • http://petrossa.wordpress.com/ petrossa

    Unfortunately not only Depression is loosely defined. One could argue that just about every major affliction is loosely defined in the diagnostic criteria manuals.

    The reason for that is simple, none of them are based on scientific methods, using empirical data. They are originally purely interpretative behavioral study based definitions adapted over time to 'resolve' conflicts between definition and reality.

    The worst one of the lot, DSM V is set to trump them all by rendering just about anything a 'spectrum'. That way you can make a valid claim base don the DSM that everyone suffers from some affliction.

    It also confound serious science, such as neuroscience when they try and find markers for a certain condition.

    The old skool psychiatry can then triumphantly say: Look your marker X doesn't cover the whole spectrum so it isn't valid.

    Anyone who isn't indoctrinated with formal education or has managed to keep an open mind nonetheless can easily recognize that most conditions are the result of an improper construction of the brain.

    Simple, just by the mere fact of the enormous complexity its impossible to be faultlessly copied over and over again. Errors MUST exist, by pure chance alone already.

    And they lead to observable differences in behavior.


  • Anonymous

    Hmm… As someone who is not an American, and was not diagnosed with severe depression until past adulthood (I was taught to dislike going to the doctor, as a kid), this strikes me as weird, though understandable I guess – considering how weird the US med system is. I have always been told by medical sources that antidepressants alone is worth very little and that it is only if you combine it with for instance CBT or some other form of therapy that the success rates actually push into 60-70%, as opposed to 20-40%. Doctors (where I have lived) tend to be pretty reluctant to prescribe antidepressants unless it's significant, and would much rather you just work on improving your life situation so you won't feel as depressed/blue. Exercise, relaxation techniques, etc… As someone for whom the meds have been a genuine life saver (I have a history of failed suicide attemempts as a kid even, not that it ever was found out by anyone out of my home) it's a bit too easy to be dismissive of people who have “mild” depression. I mean, even just herb pills/tea in mild doses work for them (whether better than placebo, I do not recall). Just dealing with their feelings is enough to lessen/remove the depression, why some people are so keen on prescribing pills for everything I don't get…

  • Art

    Given that the effects of patient beliefs about the treatment are much larger than the effects of actual treatment received, and that most of antidepressants have noticeable effects (not really blind), wouldn't that provide a complete explanation for drug/placebo difference? Isn't it a much more “dangerous truth” that antidepressants might not be effective at all and we just don't know due to methodological limitations of the current trials? Why are researchers continuing to ignore this issue and keep doing placebo controlled trials with outcome measures only based on patient reports?

  • http://www.blogger.com/profile/16203083806436919715 Bernard Carroll

    A few quick points. First, when Sheldon Preskorn says the drug-attributable rate of response to antidepressant drugs is about one in four patients, he is telling us the NNT (number needed to treat) is 4. That is correct for the early classes of antidepressant drugs, but the efficacy of the newer SSRI drugs is much less impressive, with a NNT more like 8-10. These drugs became the first line choices, especially in primary care, for reasons of safety and tolerability, not because of remarkable efficacy.

    Second, the key determinant of drug attributable response is not severity but subtype of depression. We are now seeing calls for a reinstatement of melancholia, a.k.a. endogenous depression, as a distinct disorder. Melancholia comes in mild and severe forms but it is still distinctive in its phenomenology. Unfortunately, since the generic construct of major depression appeared with DSM-III in 1980, clinicians have largely forgotten about melancholia.

    Third, the cautious reaction Sheldon Preskorn received from the academic leaders back in 1996 is further proof, if any were needed, that the KOLs of that era moving forward were ignorant of fundamental clinical therapeutics. They had been co-opted by the marketing arms of the corporations.

  • http://www.blogger.com/profile/06647064768789308157 Neuroskeptic

    Michael: That's interesting. IIRC there's not very much work on antidepressants in dysthymia, certainly not compared to the MDD literature. But actually it makes sense if you assume that what makes something antidepressant responsive is its severity – not just in the sense of how severe the symptoms are at any given time, but also how persistent they are. Maybe.

  • http://www.blogger.com/profile/06832177812057826894 pj

    “Why are researchers continuing to ignore this issue and keep doing placebo controlled trials with outcome measures only based on patient reports?”

    Because outcome measures based on clinician reports tend to find an even greater effect?

  • CatLover

    Another problem with the overselling of antidepressants is that patients who do NOT respond to them and do not get better on their own, with time, are left blaming themselves – “what is the matter with me?! These antidepressants are supposed to treat my depression.” In the case of mental illness, if you don't get better, it's because you aren't taking your meds, or you must have an unhealthy lifestyle or be borderline, because EVERYONE knows that depression is easily treated with medication. I think the repeated statements that this pill or that pill will work leads to dashed hopes and learned helplessness and even more chronic depression in a lot of cases.



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Neuroskeptic is a British neuroscientist who takes a skeptical look at his own field, and beyond. His blog offers a look at the latest developments in neuroscience, psychiatry and psychology through a critical lens.


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