Soothing the Sad Savage

In the latest New Yorker, Louis Menand reviews reasons to be skeptical of psychiatric drugs, including this stuff I teach in my health econ class:

Fifteen years ago, [Irving Kirsch] began conducting meta-analyses of antidepressant drug trials. … Kirsch’s conclusion is that antidepressants are just fancy placebos. … Drug trials are double-blind: neither the patients (paid volunteers) nor the doctors (also paid) are told which group is getting the drug and which is getting the placebo. But antidepressants have side effects, and sugar pills don’t. Commonly, side effects of antidepressants are tolerable things like nausea, restlessness, dry mouth, and so on. … This means that a patient who experiences minor side effects can conclude that he is taking the drug, and start to feel better.

But after 6000 words of such skepticism, Menand still concludes: take the meds.  Why?  Because impressive authors have written eloquent testimonials:

The recommendation from people who have written about their own depression is, overwhelmingly, Take the meds! It’s the position of Andrew Solomon, in “The Noonday Demon” (2001), a wise and humane book. It’s the position of many of the contributors to “Unholy Ghost” (2001) and “Poets on Prozac” (2008), anthologies of essays by writers about depression. The ones who took medication say that they write much better than they did when they were depressed. William Styron, in his widely read memoir “Darkness Visible” (1990), says that his experience in talk therapy was a damaging waste of time, and that he wishes he had gone straight to the hospital when his depression became severe.

The only reason Menand can imagine resisting such artists is a perverse religious desire to suffer:

What if there were a pill that relieved you of the physical pain of bereavement—sleeplessness, weeping, loss of appetite—without diluting your love for or memory of the dead? Assuming that bereavement “naturally” remits after six months, would you take a pill today that will allow you to feel the way you will be feeling six months from now anyway? Probably most people would say no. … Gerald Klerman once called “pharmacological Calvinism” … the view, which he thought many Americans hold, that shortcuts to happiness are sinful, that happiness is not worth anything unless you have worked for it.

Numbers schmumbers – only uncivilized animals, or religious nuts, would not let eloquent authors soothe their savage doubts, until they accept being comforted by their culture’s conventional ways to show that folks care.

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  • I’m going to read the article, but I’ll be ticked if he doesn’t consider the possibility that those testimonials are all the result of the placebo effect.

  • “take the meds” sounds like good advice, not undermined by the likelihood that the good results thereby achieved are due to the placebo effect.

    (Authenticity concerns are worth considering, but if anything arguably support using such means to overcome the inauthenticity of depression.)

    • Jeff

      Agreed. Robin, in his identity as against medicine, has forgotten that placebos, like drugs, are different. All those “eloquent authors” are saying that this placebo is better than those other placebos.

      • Drewfus

        would you suspect that it’s the color, or the size of the placebo that makes one better than the other?

        Do you think that competitive pressures will result in all placebos eventually being, say, big and green?

  • Violet

    Psychiatric drugs does not equal to antidepressants.

    As for antidepressants the current line of thinking is that they are good in severe depression when combined with therapy. But usually patients don’t have money/resources for the therapy.

    There are lots of bad things in the pharma industry certainly.

    I think the situation would be worse without the option of psychiatric drugs. What do you think could replace them today?

    The drugs are better than nothing.

  • I have decided to start taking homeopathic anti-depressants, thereby enjoying a powerful double placebo effect.

  • Are you kidding?

    Look what happens to our best depressed artist if they get treatment:

    Bono (U2) – HUGE wanker couldn’t write a decent song to save his life anymore
    Peter Garrett (Midnight Oil) – washed up left wing politician who yells too much
    Madonna – single handedly ruining a small african country
    Lars Ulrich (Metallica) – whiney little pissweak sook
    Red Hot Chilli Peppers: The whole band simply stinks now
    Sting – performing for Uzbekistan royalty
    Moby – making elevator music and being a fucking vegan
    Morrissey – oh wait, he’s always sucked.

    Any culture who wants some decent art should keep it’s artists repressed and angry… or at least kill them when they’re young.

  • toto

    Hm, are we not at risk of falling for the sirens of contrarianism here?

    Like, enthusiastically following the lone voice that suddenly overturned an entire field of research by reanalysing existing data in a novel way (not an impossibility, but often a sign to adjust your priors). Or trusting popular reports rather than actual scientific opinion about the research – but only inasmuch as they follow our own pre-existing opinion about said research.

    Note that Kirsch’s research has one hard, clear outcome: even using his metric of significance (more restrictive than the usual one, and perhaps not suited to the way the studies were done), meds do work “NHS-significantly” higher than placebo for highly depressed patients – see here.

    I tried to find more about other scientific opinions on this matter. I found this (useful explanations) and this (a possible explanation for the “rising placebo” effect: studies have tended to include more and more sites, which seems to have led to lower initial severity in test subjects, thus reducing the placebo-med difference).

    • lemmy caution

      Menand’s article points this out too:

      Kirsch’s claims appeared to receive a big boost from a meta-analysis published in January in the Journal of the American Medical Association and widely reported. The study concludes that “there is little evidence” that antidepressants are more effective than a placebo for minor to moderate depression. But, as a Cornell psychiatrist, Richard Friedman, noted in a column in the Times, the meta-analysis was based on just six trials, with a total of seven hundred and eighteen subjects; three of those trials tested Paxil, and three tested imipramine, one of the earliest antidepressants, first used in 1956. Since there have been hundreds of antidepressant drug trials and there are around twenty-five antidepressants on the market, this is not a large sample. The authors of the meta-analysis also assert that “for patients with very severe depression, the benefit of medications over placebo is substantial”—which suggests that antidepressants do affect mood through brain chemistry. The mystery remains unsolved.

      Read more:

  • Bradley Evans

    In double blind studies, people who take placebo do report side effects, just like they experience beneficial effects from these drugs. Confusion may arise over the name “placebo” which I think derives from “to please.”

    If the study drug regularly produces a side effect, making a double-blind study impossible, the study could have a more sophisticated comparator. For instance, if the study produced green urine in 90% of people, then you’d want, if you could get it, a comparator that produced green urine but had no other effect in the body.

  • Grant

    What does it matter if the cause of an improvement is a placebo effect or the drug itself? Sure it would be nice if we could just decide to feel better without the need for a placebo, especially one that costs money. But most people can’t do that.

    • The problem with this is that a placebo effect isn’t necessarily a real cure, and I would contend that it is unlikely that there are any real effects from placebo. Placebos control for all effects other than the active effects of the drug – most notably, I would say, reporting artifacts. If someone is more likely to report that they feel better even if they don’t feel better (possibly due to imperfect ability to compare their current state to past states), this will show up as a “placebo effect” in people who are objectively no better (and would be objectively no better if an objective measure existed).

      I would be willing to bet that you could find placebo effects in treatments of a rock to increase shininess if you performed such a study.

  • Couldn’t this problem be easily solved using placebos with some type of obvious, non-harmful, non-painful physiological effect?

    • Violet

      Placebos already have placebo-side-effects.

      Basically feeding people placebo pills makes them experience and report side effects.

    • Eliezer you need a placebo that mimics the side-effects of the active drug.
      – so your placebo has some active ingredients as well, which complicates the study (perhaps those ingredients have more side effects..)
      – and you’d need the cocktail to be licenced for the use you intend
      – and if the side effects you are mimicing are harmful there are ethical problems. eg how do you test chemotherapy against a placebo?

      it’s kind of complex.

      • Jimmy

        That’s only if the patients know what side effects to expect.

        You probably can’t get away with giving them a ‘mystery drug’, but you might be able to add a few extra “possible side effects” to the list. If you can do that, then just add on whatever side effects your new placebo has. Informing people of negligibly likely risks is standard practice anyway.

  • dWj

    Another cheer for using placebos. I understand that the common cold is particularly susceptible to the placebo effect, and that’s why there are so many home remedies. The ones I use work on me; if they don’t work on someone else just because he doesn’t believe in them, that’s really not a problem for me.

  • Nanonymous

    Way to go! That’s right, all antidepressants are nothing but fancy placebos and there is no reason for anyone taking anything. Yeah, no need to keep in mind the fact that there are a lot of different people with different responses and that there are a lot of different antidepressants with widely differing properties. Being a contrarian is a lot more important than considering the incredible complexity of the problem. Just reduce it to the point of absurdity – “antidepressants don’t and C.B.T. does work” and be done with it.

    Not exactly about antidepressants but a nice illustration nevertheless: The largest ever study of pharmaceutical treatment of alcoholism, Project Combine, compared two drugs – each with or without CBT and in combination with each other. The result: on every measure, one of the drugs was hardly doing anything, CBT was slightly effective and another drug was more effective than CBT – but only when used alone. Combining it with CBT made it essentially non-working (approximately the same as placebo and no CBT). Combining the two drugs resulted in much stronger side effects but was less effective than the effective drug alone. When given alone, the non-effective drug also gave more side effects. None of these results is possible if CBT works and pharmaceuticals don’t. (ref.: Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence: The COMBINE Study: A Randomized Controlled Trial. JAMA. 2006; 295(17):2003-17)

    • Jess Riedel

      Is Robin Hanson advocating CBT (=Cognitive behavioral therapy?)

    • Speaking as someone who has suffered form depression that’s no excuse to insist that they aren’t placebos. Of course if you don’t have bad habits of reading up on the medical literature for drugs you take like I do that placebo effect might do you some good so go ahead and take em.

      As for what else you could do. Well if the pyschiatric community really faced this problem they might start prescribing drugs with clear anti-depressant effects like Adderall. Sure there is abuse potential but that’s not a reason not to give a person a shot at happiness or to pull them out of a suicidal spiral.

  • At the end of your Double Blind Randomised Controlled Trial you open the envelopes and half of your control group died. Sad, but typical. Pressing on, you find that half of your treatment group died. That is a huge disappointment: the drug did nothing at all!

    That is the usual interpretation, but it is wrong. It may well be that the drug did nothing at all, but the result of the trial is logically weaker. The drug did nothing OR it re-rolled the dice, curing some who would have perished and killing an equal number who would have recovered on their own.

    That leaves the medical researcher with a dilemma. Horn One: reject the hypothesis that made the trial seem worth running and go in search of a different drug with a new mechanism. Horn Two: reject the hypothesis that the patient population is homogeneous and go in search of a diagnostic test that will tell you in advance who you will kill and who you will cure.

    What extra information might make Horn Two look best? Testimonials are obviously consistent with the drug curing some patients who would otherwise have perished, but testimonials are in practice quite consistent with drugs that do nothing at all. Anti-testimonials are more interesting, because anti-testimonials to drugs that definitely do nothing, such as homeopathic remedies, are rare. Anti-testimonials to antidepressants are common.

    What should a depressed person do if they accept that antidepressants are a feeble medicine overall, but they also accept the package of testimonials and anti-testimonials as pointing strongly towards Horn Two? It is reasonable to believe the testimonials and try taking the drugs, but that is the playing-with-fire option. Given the disappointing overall results, the more you believe in the testimonials, the more you should also believe in the anti-testimonials, and you should have a correspondingly greater wariness that you might be harmed rather than helped.

    • Jess Riedel

      …anti-testimonials to drugs that definitely do nothing, such as homeopathic remedies, are rare. Anti-testimonials to antidepressants are common.

      Isn’t that because homeopathic remedies do nothing, but antidepressants screw with your brain chemistry? Just because the antidepressants have bad side effect doesn’t make Horn 2 particularly more likely (unless you say “well, it screws with my brain, and my depressions is inside my brain, therefore it’s more likely to be effecting my depression than if I had no side effects”.)

  • Alan

    Don’t most of these trial have retrospective queries, so that participants can tell the trial which arm they thought they were in? This allows for the “placebo-reveal” effect to be determined. Thus you could throw out a trial in which everyone correctly guessed which arm they were in. This is fairly standard practice currently, I don;t know if some of these older trials used this.

  • andrew

    whether or not these drygs work, and i think some of them do (particularly citalopram) help to relieve frustration and anger, i just don’t feel the side-effects are worth it

    i’ll tell you this, i took citalopram for 3 months. for the entire first month i constantly felt like i was coming up on ecstasy. god knows what i would’ve thought was happening to me if i had no experience of illegal drugs.

    that and the fact that i was basically sedated, felt no anger at the usual unreasonable things that make me angry (abusive customers, fascist street gangs marching in my country, etc) and was basically impotent for the entire period has convinced me never to touch psych drugs ever again.

    and you’d better believe that if you’ve basically been high on E for 3 months, the come-down is HARD, and it lasts for weeks

    again, luckily, i’ve got experience with drugs, and i know what to expect. someone who didn’t might very well find themselves in very dangerous and unknown psychological territory

    that’s not to say that properly prescribed anti-depressants might not be helpful for people with severe depression. but over here they hand the things out like sweeties

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  • I do believe that a number of antidepressants have been shown to help a lot with suicidality, but not with the overall depression. That’s definitely my experience.

  • Phil Goetz

    At some point, Robin, you need to start asking what the expected value of your posts are. This one has some chance of saving someone from a needless expense of $20-$200 to try out antidepressants, and some other chance of encouraging someone to go off their meds, after which they kill themselves or someone else. My estimate is that the expected-value ratio here is many orders of magnitude in the wrong direction. I wonder if you’re going to attack vaccination of children next.

    Controlled studies are not and should not be the sole arbiter of truth.
    Controlled studies are especially important in healthcare, because biases, illusions, wishful thinking, and placebo effects are so strong. But they also fail most dramatically in healthcare, mainly because individual reactions differ so much. The assumptions underlying standard statistical analyses don’t apply to human biology or psychology, which never have the simple distributions that the analysis requires.

    When one person can repeat something many times and have an observable effect each time, then we need to take their anecdotes seriously. For instance, I get a headache from drinking two sodas with Aspartame in a row. Any respectable MD will swear up and down that this is impossible, because many controlled studies have shown that Aspartame has no ill effects. Nonetheless, my own personal experience is repeatable and reliable.

    In other cases, say orthoscopic surgery, where an individual doesn’t get repeated trials, we don’t have any way to observe individual variation other than in large studies. In that case, believing the results of large studies is more appropriate than believing the impressions of doctors who have never bothered to actually count how many patients said they felt better afterwards.

    • No, the benefit is forcing the public to face the fact that we don’t have nice tidy solutions for depression and making them tackle the hard decisions like whether to use mood boosting agents (long considered not really anti-depressants since they treat more than depressed people).

      More fundamentally the failure of antidepressants represents a serious challenge to the disease model of depression. We need to start taking seriously the possibility that depression is the bad end of a distribution. Depression may be something much more like height or amount of body hair, a natural variation (affected by environmental factors) which we think requires treatment in some cases, e.g., excessive body hair or severely inconvenient shortness.

      This issue poses a fundamental moral dilema to the human species. If depression can’t be easily fenced off as abnormal brain function when do we use psychoactive substances to alleviate suffering? I think the answer is whenever they prevent more suffering than they cause and the myth of antidepressants is one of the things that is holding us back from developing useful agents of this kind.

      Finally saying people are individuals and vary is find and dandy but that still doesn’t provide you evidence the drugs are a net help. Heck, those individuals differences could just as well work out in the other direction. Now certainly there are some areas where despite good evidence from controlled studies we can reasonably assume that a given treatment is likely to be helpful to certain patients on the basis of a sound theoretical model but that is distinctly lacking for anti-depressants.

      Ultimately though the question isn’t whether anti-depressants help some people but WHY. Is it a placebo effect or some other mechanism. Personally I suspect the remaining statistically significant effects for the very depressed result from regression to the mean (if you are way on the unhappy side then randomly fuck with your brain function and your more likely than not to end up a bit happier).

      But Robin’s point still stands. It’s not an excuse for poor reasoning.

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  • Drewfus

    The concept of regarding a placeo group as being akin to a control group is fundamentally flawed. A control group – a notion that is very applicable to the physical sciences – has no natural equivalent in psychiatry or psychology, due to unavoidable social interactions.

    To elaborate – the placebo group is not just swallowing pills, but is also receiving positive attention, and therefore social support, from those who administer the treatments to them. People are showing that they care. This could make a huge difference, and i would suggest the social solidarity that is evident in the actions of the non-patients in these trials is the real placebo.

    So we really have three factors at work in these trials:

    1. anti-depressants
    2. placebos
    3. social solidarity

    Both groups are receiving significant doses of either 1 and 3, or 2 and 3, and therefore the scientific ideal of altering one variable while holding all others constant is not obtained.