A “Severe” Warning for Psychiatry

By Neuroskeptic | January 24, 2010 8:25 pm

Imagine there was a nasty disease that affected 1 in 100 people. And imagine that someone invented a drug which treated it reasonably well. Good work, surely.

Now imagine that, for some reason, people decided that 10% of the population need to be taking this drug, instead of 1%. So sales of the drug sky-rocket. Eventually some clever person comes along and asks “This is one of the biggest selling drugs in the world – but does it work?” They look into it, and find that it doesn’t work very well at all. For about 9 out of 10 people, it’s completely useless! What a crap drug.

Of course the drug hasn’t changed, and what’s crap was the decision to prescribe it to so many people.


Back to reality. According to accepted DSM-IV diagnostic criteria, close to 50% of people suffer from a mental illness at some point; a large fraction of this being depression. 10% of Americans took antidepressants last year according to the best estimates.

Guess what? Clever people have started asking “Antidepressants are amongst the biggest selling drugs in the world – but do they work?” And their answer is – not very well. The latest such claim came from Fournier et al and appeared in JAMA a couple of weeks ago: Antidepressant Drug Effects and Depression Severity.

These researchers re-analysed the data from six clinical trials testing antidepressants against placebo pills. The drugs were the tricyclic imipramine and the newer SSRI paroxetine. The total sample size was a respectable 718, and most trials lasted 8 weeks, which is longer than average for this kind of study. Here’s what they found –

Grey circles are people on antidepressants, white circles people on placebo. What this shows is that the more severe the patient’s depression, the more they get better – when they’re given either drugs or placebos. However, because the improvement on antidepressants rises more steeply, the benefit of antidepressants versus placebos correlates with severity. The thin blue line marks the minimum severity for which the average effect of the drugs over placebo was “clinically significant” according to NICE criteria (although these are arbitrary).


So, this study says that antidepressants work better in more severe depression. This is not a new claim – Kirsch et al (2008) famously found the same thing, and long before that so did Khan et al (2002). However this new analysis has some advantages over previous ones. First, Fournier et al looked at what happened to each patient individually, whereas the previous studies found that in trials where the patients were more severely depressed, on average, antidepressants worked better.

Second, the patients in this analysis spanned a wide range of severity scores, from 10 points on the Hamilton Scale to nearly 40. In Kirsch et al almost all the trials had average severities in the narrow range of 22 to 29. Finally, none of the trials in the new paper used a placebo run-in period. These are meant to exclude people from the trial if they improve “too well” during an initial week or so of placebo pills. In theory, they bias trials against finding large placebo effects; it’s not clear they actually work, but either way, it’s good to know it wasn’t a factor.


Overall, the evidence all seems to point to the idea that people with more serious clinical depression respond better to antidepressants vs. placebos in clinical trials. The exact details are debatable, there’s the issue of whether antidepressant clinical trials are realistic, and the question of how clinically effective antidepressants are is also controversial, but I’m not aware of any studies which have contradicted this central claim.

But when you start to think about it, this is a very odd result. Fournier et al say that

The general pattern of results reported in this work is not surprising. As early as the 1950s, researchers conducting controlled investigations of treatments for a wide variety of medical and psychiatric conditions described a phenomenon whereby patients with higher levels of severity showed greater differential (i.e., specific) benefit from the active treatments.

and refer to a couple of papers from the 1960s. But I must admit that I do find this very surprising. We don’t wait until someone’s nearly dead from a bacterial infection before we give them antibiotics, we give them early, when the disease is still mild. Doctors unfortunately don’t tell people “Good news! You’ve got advanced-stage cancer – just the kind where drugs work best.” Why is depression so different?

Look a little closer, and a possible answer emerges. Severity, in all of these studies, was measured using the Hamilton Rating Scale for Depression (HAMD). The HAMD has 17 items, and each asks whether you’re suffering from certain symptoms; the more symptoms you have, and the more pronounced they are, the higher your total score. You get 1 point if you have “occasional difficulty falling asleep”, 2 points for “nightly difficulty falling asleep”, 4 points for “Hand wringing, nail biting, hair-pulling, biting of lips”. Here’s the whole thing.

The HAMD was designed in 1960 by a psychiatrist, Max Hamilton, and it was originally intended for use by staff at psychiatric hospitals for use on depressed inpatients. So it’s not a measure of severity per se: it’s a measure of how well your symptoms match those considered to be characteristic of severe depression in 1960.

Psychiatry’s concept of depression – not to mention the wider culture’s – has changed greatly since then. 1960 was a full 20 years before the DSM-III criteria of depression were published, which form the basis for today’s DSM-IV criteria. A quick comparison of the DSM-IV alongside the HAMD reveals a lot of differences. It’s quite possible to meet DSM-IV criteria for “Major Depressive Disorder” yet score low on the HAMD.

Which brings us back to the imaginary scenario at the start of this post. My personal interpretation of results like those of Fournier et al is this: antidepressants treat classical clinical depression, of the kind that psychiatrists in 1960 would have recognized. This is the kind of depression that they were originally used for, after all, because the first antidepressants arrived in 1953, and modern antidepressants like Prozac target the same neurotransmitter systems.

Yet in recent years “clinical depression” has become a much broader term. Many people attribute this to marketing on the part of pharmaceutical companies. Whatever the cause, it’s almost certain that many people are now being prescribed antidepressants for emotional and personal issues which wouldn’t have been considered medical illnesses until quite recently. (Antidepressants also have a long history of use for other conditions, like OCD, but this is a separate issue.)

My imaginary story used made up numbers: I’m not saying that only 10% of the people on antidepressants have “classic” depression. I don’t know what the % is. But apart from that, in my opinion (and I don’t think I’m alone), it’s far from fantasy.

ResearchBlogging.orgFournier, J., DeRubeis, R., Hollon, S., Dimidjian, S., Amsterdam, J., Shelton, R., & Fawcett, J. (2010). Antidepressant Drug Effects and Depression Severity: A Patient-Level Meta-analysis JAMA: The Journal of the American Medical Association, 303 (1), 47-53 DOI: 10.1001/jama.2009.1943

  • http://www.blogger.com/profile/07089940693723268558 Lizardo Cruzado

    This comment has been removed by the author.

  • http://www.blogger.com/profile/08461338194309128443 Paul


    Just to clarify, is a placebo washout the same as a placebo run in?

  • http://www.blogger.com/profile/01692499159236632642 woly

    So would you say that the main take home message here is that the current DSM criteria for depression is too broad?

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

    paul: Oops, that was a typo. I mean run-in. Fixed.

  • Anonymous

    I think marketing has obviously led to the over prescribing of antidepressants. Just watch some daytime TV in the US and you will be bombarded by ads for psychotropics, including antipsychotics. It is absolutely nuts! But somebody should figure out exactly how the placebo effect occurs; bottle it and make a zillion dollars!

  • Anonymous

    A nice review and in depth discussion of the problems linked with the use of DSM-iv (increased reliablity, insufficient validity) and the repercussions on the clinical use of antidepressants can be found in
    “prescriptions for the mind: a critical review of contemporary psychiatry” by Joel Paris.

  • http://www.blogger.com/profile/08461338194309128443 Paul


    Sorry NK, I didn't mean to sound pedantic there, I genuinely didn't know. So a placebo run-in is when they place everyone in the trail on a placebo over say two weeks and get rid of the people who respond to the inert substance. Am I right in saying then, that a wash-out is when they have those in the trial taken off existing medications? I seem to remember a chapter in 'Mad in America' by Robert Whitaker that raised concern about how those who conduct trials go about this procedure.

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

    Paul: No, it was my mistake. A placebo run-in period is as as you describe – it's designed to exclude “placebo responders” from the trial in the hope that this will make the drug seem more effective.

    It's basically a way of biasing the trial in favour of the active drug – and as such has attracted quite a bit of criticism – but it's not clear it actually works, I remember reading a large meta-analysis where trials that did it gave the same results as ones that didn't. So it's probably just a waste of time.

    A washout period is where you stop whatever medications people were on, before starting a new treatment.

  • http://www.blogger.com/profile/08461338194309128443 Paul

    Yes, I too have read an analysis, probably the same one, that found placebo run-ins made no difference (I say read, but I don't think I could get past the pay wall.

    However, although I believe this procedure to be suspect, don't 'they' claim to do these run-ins to find out, and then weed out, individuals who are poor adheres.

    Here's an interesting article related the the topic:

    An empirical evaluation of the placebo run-in.


  • http://www.blogger.com/profile/09374512270335764119 Maia Szalavitz

    What this leaves is out that it's abundantly obvious that antidepressants work fabulously “Listening to Prozac” style well for some tiny group of people– and make another tiny group suicidal and or even homicidal.

    This means that the rare extreme positives and rare extreme negatives and not so rare modest positive and not so rare modest negative responses wash each other out. David Healy has looked at this– which is why he (no drug company apologist!) still supports use of the meds in many cases.

    These meta-analyses completely miss this– but this is why the media coverage is so polarized with some seeing demon drugs and some seeing panaceas in the same exact substances. If the drugs were really close to placebo in individual cases, you wouldn't have this love/hate stuff.

    What we need to find out is which people will do well on which drugs– but the “too close to placebo” case against them is really missing the point.

  • Anonymous

    First off, I love your blog. It is top notch. And I understand your argument about the “broadening” of the criteria for clinical depression in DSM and how this differs from the days when the HAMD was developed as to criteria for “major depression.” But I can't help but thinking that the JAMA study findings (and others like it)speak to the larger issue of the inadequacy of a strict medical model of psychiatric “disease” or at least major depression. You are right– it is paradoxical that drug treatment for depression only “works” in very severe cases. From this you seemingly infer that “mild” or “moderate” cases are not really afflicted with a pathological disease process. This makes no sense. Virtually all major illnesses in clinical medicine recognize severity and stages of disease progression. We speak of “mild” cases of HTN, diabetes,heart failure, MS, blah blah, blah — the list in endless. We have stages for cancer. And these disease entities, with varying degrees, respond to early intervention beyond what can be achieved with placebo. To suggest that “mild” or “moderate” cases of depression are not really clinical depression in an early stage seems weird. Are you advocating a use of categorical classification of mental illness? Like, you are either COMPLETELY nuts, or not nuts at all?

  • http://mindhacks.com Vaughan

    It seems quite reasonable to me that antidepressants would 'work better' in HAMD rated severe depression than moderate-mild depression because the scale gives a single number which actually reflects a wider number of symptoms more than the severity of one along a dimension.

    In your example, imagine if the severity of a bacterial infection was rated not by the amount of bacteria but by clinical symptoms (1-3 points for fever; 1-3 points for headache; 1-3 points for swelling etc). In this case, the drugs are likely to work 'more effectively' in 'more severe' infections, because there will be larger drop in the number of different clinical symptoms (clinical signs, to be pedantic).

    Compared to more recent depression scales, the HAMD has a much greater focus on 'somatic' rather than 'psychic' symptoms, to use the terminology of the time, and it became popular when widely adopted by the pharmaceutical industry to test the tricyclics which have significant sedating and anxiolytic effects.

    The fact that SSRIs also have anxiolytic effects may mean that they are more likely to reduce HAMD severe depression by their general reduction of somatic symptoms, which I suspect (but we can't be sure without an odds ratio analysis) are more prevalent in high scorers.

  • Anonymous

    Remember the old dichotomy,
    “endogenous depression”
    “neurotic depression”?
    At the time I was taught that only one responded to antidepressants, the other to therapy. This was in the 80's, back in the day of tofranil. People thought long and hard before pushing tca's. Now we should think long and hard before pushing ssri's for depression.

    We have come 100 percent full circle in 30 years, haven't we.

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

    Anonymous: Right. The subtext of my post (and indeed a lot of my posts) is “It's time to bring endogenous back”…

  • http://www.blogger.com/profile/09374512270335764119 Maia Szalavitz

    I don't see how bringing endogenous back helps– there's people in both categories who will benefit and people in both categories who won't. No one really knows the difference.

    So long as you aren't using something like Paxil which has serious withdrawal issues, I don't see why people should be left to even-less evidence-based talk therapies (at least as actually practiced: just try finding someone who actually practices a therapy like CBT or IPT the way it is in the manual)

    Bad talk therapies can be just as harmful as drugs by doing things like pushing rumination, re-traumatizing people who've suffered trauma, telling people to drop important relationships or not seek them (“you can't love until you learn to love yourself”), etc. etc.

    Why should people who suffer mental illness have to suffer through more invasive, time-intensive, less supported talk therapies when drugs might work? Let people choose–if they want talk, fine– but if you look more closely at the data, it's very clear that there are some strong positive responders, some strong negative responders and that this accounts very well for all the paradoxes about these drugs, ie, they're wonderful, they're terrible, they're placebo.

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

    Maia: No disagreement there – I've never said or thought that instead of giving tens of millions SSRIs, we should be giving tens of millions CBT. We probably shouldn't be treating tens of millions of people for mental illness at all, because mental illness isn't especially common.

    That's what I meant about bringing “endogenous” back; DSM-IV counts you as suffering from a psychiatric disorder, MDD, if you display some depressive symptoms, but it's becoming clear that the majority of people display these symptoms at some time or other, in response to life events.

    Treatments don't help people who aren't ill, and indeed labeling non-medical issues as illnesses to be treated (whether with drugs or therapy) can be actively harmful. Whereas it's hard to deny that at least some cases of “endogenous depression” are illnesses.

  • http://www.blogger.com/profile/09374512270335764119 Maia Szalavitz

    Thanks for the reply!!!!But why wouldn't mental illness be that prevalent when physical illness affects similar proportions of the population? Do we expect the most complex object in the known universe to be less prone to dysfunction than say, the heart or the lungs?

    If people were coming to doctors after having suffered 2 weeks of symptoms like it says in the DSM, I would worry about overdiagnosis– but usually, people wait years before seeking depression treatment. I've seen the devastating results of that– and they are much worse than taking a medication that you don't need for a few weeks and deciding that the side effects aren't worth it (which is what most people do with SSRI's).

    At the same time, I definitely agree that labeling something as an organic disease and putting the sick role on people is problematic when indeed, social support plays such a critical role in recovery.

    We still haven't figured out how to deal with the fact of the social brain and have medical mental illnesses– and clearly that's what you're grappling with here, too, no?

  • Anonymous

    Unfortunately, I am getting to be an old timer in this field. Oh! Let me cognitively re-frame that! I am getting to be a “seasoned veteran” in this field! Presto! I feel less depressed already! Seriously, I too remember being taught about the distinction between endogenous and exogenous or “neurotic” depression. The more I see, the more I agree with Neuroskeptic. And the fact of the matter is that there are instruments available, at least in the US, that effectively distinguish between these two major forms of depression. For example, the Personality Assessment Inventory (PAI) developed by Morey is an elegant way to profile the different ways that “clinical depression” can manifest in individuals. Let's face it: Not all clinical depressions are alike. You have people who have prominent neurovegetative signs combined with dysphoria, but they don't have the Beck negative thinking sets. You have people with prominent dysphoria and negative thinking, but without marked biological signs ( sleep, appetite, libido, energy, etc). Both types may score equally high on a summary scale or total score of depression severity. And both types might be equally suicidal. But it is possible (actually likely) that one group will respond better to medication and the other group will respond better to CBT. Drug trials do not account for these different presentations and as long we live in fantasy land and insist that depression is homogeneous in presentation, we are doomed to the continuing debates spurred on by the lack of overall or group significant differences between placebo and meds in standard drug trials. Treatment has to be tailored to the individual presentation!

  • http://www.blogger.com/profile/09430363095564651378 Grumpy Biomed

    Hm, that was a very interesting read, cheers for that.

  • http://www.blogger.com/profile/15159013165514008872 woodchopper

    Yes, very interesting. Thanks.

  • http://www.blogger.com/profile/03928365682331811860 wichitarick

    Hi not High
    There is a major danger when these meds are given to so many people .
    It takes weeks even months for these drugs to “balance” in our body's/minds.
    I won,t pretend to be a phych. scholar or even a brain/neuro working on my masters.
    But I have years of first hand knowledge of mind/mood altering drugs from a user/abuser side
    More years of sobriety has taught me the other side of my mind .
    More years of being prescribed A.E.D,S (anti epileptic drugs)and dealing with the extreme side effects from them.
    More recently being prescribed different types of “anti” depressant meds and aed,s and the crossover and side effects of these drugs.
    The reason for that gibberish is using myself and the 100 or so people I have observed I can show the most dangerous part of these drugs is the serious LACK of follow up care that IS occurring while a patient is taking the drug.
    The most dangerous part of the drugs is,nt when we become stable on them it is when we are stabilizing on the med. or when a person just quits OR in my case simply forgets to take them OR takes one pill instead of 2 or drinks or does other drugs and all this “crazy” mix is in our allready fogged mind.
    I do not gamble.
    BUT I enjoy predicting the future.
    I can and so can all of you.
    A boxing match , O.K.
    In this corner I have a wife and a child AND a bartender AND a patrons from a small town V.F.W. club.
    The other corner I have a medium weight, very strong , usually well mannered middle aged man.
    That just happens to be a veteran with p.t.s.d. and seizures that just lost his job and stayed awake for 24 hrs. FORGOT to take his meds and went back to drinking AGAIN and was sick of his wife and kid bitching all the time .
    The ringing in his ears did not help either or the sudden crash from the missed meds
    SKIP a few hours and he is in the V.F.W. listening to their b.s. “AGAIN” and THEIR problems OH WAAAA!
    well folks WHO are you betting on ?
    UPDATE ! The law only allows he get 5 days in patient phych. care and is released to start the meds over AGAIN a little AED a little anti-? a little sleeping pill because we know how GRUMPY he gets without these, Right?
    He is depressed now and the added pill to the new aed,s and the little sleeping pill are great when he is stoned from them.
    UPDATE he is court for the first boxing match and has a massive gran mal seizure and is hospitalized and crashes because the doctors do not know his “pill” count and he is given a different dose of aed,s AND a Valium
    But he has done nothing wrong AND has no insurance so he is released from the hospital and given a ride by the only person who still speaks to him .
    His old drinking buddy and they start on the 12 pack in the back seat hmmmm.!
    Boxing match again ? ANY BETS?
    Moral of the story we need serious follow up care for all the mind altering drugs .
    Do you want some real case studies ? Go spend a few days in the smoking area of your nearest V.A. hospital or read a few 100 peoples seizure diary's.
    I usually apologize for rambling but I think I said it pretty well this time. “any bets” Rick

  • http://www.blogger.com/profile/08461338194309128443 Paul

    I do understand your concerns about following individuals up when they have been prescribed psychiatric drugs. I to have some first hand experience in that I got such little help from my doctor when I was ready to come off Venlafaxine. He said just drop the dose every two weeks, however, in the end it took (a difficult) nine months.

    I actually had another opportunity (lucky me) to come off venlafaxine last year, only this time, my G.P. has a special interest in mental health and so was knowledgeable of how best to wean me of the SNRI (cross tapering to a drug with a longer half-life of course) and had me visit his surgery for advice and support. Only took me a month and a half this time.

    Interestingly, in my work as a student mental health nurse, I have to deal with a lot of patients who are told to come of an antidepressant, given an abrupt reducing regime, and told nothing of the troublesome withdrawal symptoms they are likely to experience (which are often interpreted by the patient, and sometimes the psychiatrist, as the returning of their mental health problem).

  • Left Coast Bernard

    Depression is a serious illness with often fatal outcomes.
    There are recognized treatments, medical and others.
    Why is it ethical to design studies such as the ones you cite with two arms: new therapy and no therapy?
    In cancer trials, the researchers must compare the best available therapy with the best available therapy plus the new therapy.
    Why aren't depression researchers required to do the same?
    Also, comparing powerful psychoactive medications with a placebo compromises the design because both the patients and the researchers are likely to detect which subjects have the placebo.

  • http://www.starcraft2strategyguidereview.net/shokz-guide-review shokz guide review

    I've never seen the problem from this point of view. Right, there are many more people taking drugs than those who actually suffer from the targeted illness, but shouldn't the studies first of all analyse whether or not the drug-taking patient actually suffers from the disease? I guess it always depends who pays for the study 😉

  • http://www.blogger.com/profile/14108016800554557555 kfp

    All I know is nothing works for me. No matter what I take or no matter how much talk therapy, I'm always down. No motivation to speak of. It's a miserable existence. I wish science could find out why.

  • http://www.blogger.com/profile/09374512270335764119 Maia Szalavitz

    Kfp, please don't give up. Sometimes it takes many, many tries before you find something that works. Keep following news about new treatments and make sure you are seeing someone who is willing to help you try until you get better.



No brain. No gain.

About Neuroskeptic

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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