Everybody Expects the Placebo Inquisition

An unexpected gem from last year's Journal of the American Psychoanalytic Association: Mind over medicine.

Surprisingly, it has nothing to do with psychoanalysis. Rutherford and colleagues performed a meta-analysis of lots of clinical trials of antidepressants. Neuroskeptic readers will be all too familiar with these. But they did an interesting thing with the data: they compared the benefits of antidepressants in trials with a placebo condition, vs. trials with no placebo arm, such as trials comparing one drug to another drug.

Why do that comparison? Because the placebo effect is likely to be stronger in trials with no placebo condition. If you volunteer for a placebo controlled trial, you'll know that you've got (say) a 50-50 chance of getting inactive sugar pills. You'll probably be uncertain whether or not you'll get better, maybe even quite worried. On the other hand if you're in a trial where you definitely will get a real drug, you can rest assured that you'll feel better - and that in itself might make your depression improve.

The paper only presents very preliminary results, but they say that:

Our group at Columbia has completed preliminary work involving metaanalyses of randomized controlled trials comparing antidepressant medications to a placebo or active comparator in geriatric outpatients with Major Depressive Disorder (Sneed et al. 2006). In placebo controlled trials, the medication response rate was 48% and the remission rate 33%, compared to a response rate of 62% and remission rate of 43% in the comparator trials (p < .05). The effect size for the comparison of response rate to medications in the comparator and placebo controlled trials was large (Cohen’s d = 1.2).

They only looked at trials of old age patients, but the same probably applies to everyone else.

Why does this matter? The authors suggest one very important implication. There are quite a few trials nowadays comparing the effects of psychotherapy, medication, neither, or both. How it works is that everyone gets pills, 50% of them real drugs and 50% placebos; also, half the people get psychotherapy while the others remain on the waiting list.

These trials often find that medication plus psychotherapy is better than just medication alone. This has led to the idea that therapy and drugs should be combined in clinical practice, a message which goes down really well, because it gives both psychopharmacologists and therapists the feeling that they have an important job to do. An example of this kind of trial is the influential TADS from 2004, finding that Prozac and therapy both work in depressed teens, and combining them is best. Everyone's a winner.

But as Rutherford et al. point out, there's a problem with this reasoning. The people who only get antidepressants don't know that they're getting any treatment, because they might be getting placebo. But the people who get antidepressants and therapy know that they're getting at least one real treatment (therapy). This is likely to improve their outcome through an expectation effect. (In fact, for some reason, in TADS, the people on combination treatment were told that they were getting both - they specifically knew they would never get dummy pills - which will have made this even worse.)

Now you could say that this doesn't matter: TADS and similar studies show that therapy and medication is better than just medication, and it's purely academic whether that's "just a placebo effect". But the key point is that in real life people always get medication knowing that it's real - so, like the therapy plus medication people in the trials, they get the benefit of the certainty that they are getting a real treatment. In the trials the medication-only group don't know that, but in real life they do - so the benefits of adding psychotherapy might be less, or even zero, in real life.

The authors of the TADS study did acknowledge this in their original paper, but only very briefly - here's all they say about it:

Blinding patients in the placebo and fluoxetine alone groups but not in the CBT alone group (participants knew they would not be receiving fluoxetine) and the fluoxetine combined with CBT group (participants knew that they would be receiving fluoxetine) may have interacted with expectancy effects regarding improvement and acceptability of treatment assignment.

Yet this limitation means they, strictly speaking, all TADS showed is that Prozac works in this group. It doesn't prove that adding (very expensive) therapy benefits anyone, in the real world. This is not to say that psychotherapy doesn't work of course, maybe it does, but the point is that therapy + medication trials may be best without a placebo.

Rutherford, B., Roose, S., & Sneed, J. (2009). Mind Over Medicine: the Influence of Expectations on Antidepressant Response Journal of the American Psychoanalytic Association, 57 (2), 456-460 DOI: 10.1177/00030651090570020909

Meowvolutionary Psychology

You know that thing cats do when they rub up against your legs? Did they evolve to do that?

The most sensible answer is probably "who cares, it's cute", but bear with me; a closer examination of this adorable behaviour sheds light on some more serious questions.

On one level, they obviously didn't. Cats have only been domesticated since maybe 8,000 BC. For millions of years prior, they evolved to live and hunt on their own, never interacting with humans. Domestication has led to some changes in the cat's behaviour - compared to wildcats they are generally tamer around humans, unsurprisingly - but no-one bred cats to rub up against our legs.

But on another level, evolution must be responsible. Cats all around the world do it, and we don't teach them to do it, they just decide to spontaneously. Maybe we sometimes teach them that it works for getting food, thus making them do it more often, but we don't give them the idea originally. It's an "innate" behaviour.

As I see it, leg-rubbing is based on the cat's instinct for scent-marking objects by rubbing the side of their heads against them (they have glands there although we humans can't smell them). My cats love doing this to chairs, table legs, etc. This behaviour evolved as a way for wildcats to mark out territories etc. They also like to rub up against other friendly cats as a social behaviour, probably as a way of making the whole "herd" smell the same. They do it to your legs, because in their minds you're a member of their herd... or maybe just because your legs are a bit like a chair.

Either way, leg-rubbing is an evolved behaviour, but cats didn't evolve to do it; they do it because of the interaction between their natural instincts and their artificial environment. This goes for a lot of other things too. Cats didn't evolve to drink cow's milk from bowls, they evolved to drink water from puddles, but they drink milk from bowls because evolution decided to make them like (cat's) milk (much like cow's milk), and to drink from wherever they need to. They didn't evolve to play with string, they evolved to catch mice, but... and so on.

How about us? I think the same, broadly speaking, applies. Of course we are unique amongst the animals in having human intelligence, language, conceptual thinking, etc. We are not just domesticated chimps, right? But this doesn't mean we're entirely unique. We have the same drives and emotions as other animals (maybe more, but surely not less), and the same brain mechanisms underly them. This is why if you give a mouse anti-obesity drugs they lose weight, and if you give them Valium they chill out.

One way of thinking about the human situation is that we are indeed just domesticated chimps, but with the catch that in the process of "domestication" we found ourselves transported into an entirely new environment: a more complex world. That's what having a more intelligent brain does for you, really - it expands your world. Compared to a chimp, still less a cat, we inhabit another planet entirely. But the old drives are still operating: we just have new ways of trying to satisfy them.

Here's an example. Few things are more uniquely human than modern surgery - animals can't do it (although my cat is quite good at cutting things open, his patients rarely survive), and it requires a huge amount of forward planning and accumulated knowledge. Of course we didn't evolve to perform operations.

But when a surgeon does cosmetic surgery, they're nevertheless obeying evolution. We find certain patterns of facial shape more attractive than others, e.g. we generally like symmetry, youthfulness, sexual dimorphism, and these preferences are largely innate. Presumably, these preferences evolved to make us want to have babies with people carrying "good genes" of the correct reproductive age. We didn't evolve to modify faces surgically, but cats didn't evolve to rub our legs. The same preferences that have guided the eye of eager singles for millennia now guide the surgeon's hand.

Does the whole of human culture consists of us trying to satisfy our primitive desires with our newly intelligent brains? I don't know. It certainly seems a big stretch to say that all art, politics and music are based on "primitive" preferences. But maybe it'll always take a big stretch to explain all that.

Monoamine Shock

Electroconvulsive therapy (ECT) is a crude but effective treatment for depression. It consists of applying a brief alternating current to the brain in order to induce a generalized seizure, which usually lasts for less than half a minute. It looks nothing like the picture to the left.

ECT is typically given three times per week, and a dozen sessions are enough to produce a dramatic improvement in depression in most cases. However, how it works is entirely mysterious. There are plenty of theories. An important little study from Duke University psychiatrists Cassidy et al (including Bernard Carroll) has just ruled out one of them.

Monoamines are a class of neurotransmitters: serotonin, dopamine and noradrenaline. They're involved in various aspects of mood, although the picture is very complicated, and almost all antidepressant drugs target one or more monoamines. Could ECT act by increasing monoamine levels? It's as good a theory as any, and there's some evidence for it.

However, Cassidy et al's data suggest it's not the case. They took 9 volunteers who had been severely depressed, but had recently responded well to a course of ECT. They gave them combined serotonin depletion, with the tryptophan depletion method, and dopamine/noradrenaline depletion with the drug AMPT. As a placebo comparison, they used diphenhydramine, aka Benadryl, a mildly sedative antihistamine; this is because AMPT is a sedative, and they wanted to control for active placebo effects. Few psychopharmacology studies are so well controlled.

These depletion techniques, given separately, are known to cause temporary relapses in about 50% of people who've responded to antidepressants targeting the corresponding monoamine, and also in some people who used to be depressed but are no longer taking medication. If monoamines are involved in the response to ECT, depleting all of them at once should definitely cause relapse.

What happened? Nothing. No-one experienced even a partial return of their depression with either the real or the placebo treatments. These depletions don't put levels of the neurotransmitters down to zero, but Cassidy et al. used the same doses that have caused dramatic relapses in susceptible people.

This strongly suggests that monoamines are not required for the clinical response to ECT, at least not in any straightforward more-is-better way. Given that ECT works faster than antidepressants and more often (the controversial side effects are the main reason it's used only as a last resort), this is a blow for the monoamine hypothesis of depression... like I said, it is complicated.

And how does ECT work? We still don't know. This study narrows down the possibilities.

Cassidy, F., Weiner, R., Cooper, T., & Carroll, B. (2010). Combined catecholamine and indoleamine depletion following response to ECT The British Journal of Psychiatry, 196 (6), 493-494 DOI: 10.1192/bjp.bp.109.070573

Serial Killers

Much of Britain is currently following the trial of Steven Griffiths, or as he'd like you to refer to him, the Crossbow Cannibal.

Serial killers are always newsworthy, and Griffiths has killed at least three women in cold blood. (He did use a crossbow, but I think the newspapers made up the cannibalism.) But it's Griffiths's interests that have really got people's attention.

It turns out that before he became a serial killer, he was a man obsessed with... serial killers. His Amazon wish list was full of books about murder. He has a degree in psychology, and he was working on his PhD, in Criminology. Guess what his research was about.

Griffiths is therefore a kind of real life Hannibal Lecter or Dexter, an expert in murderers who is himself one. He's also a good example of the fact that, unlike on TV, real life serial killers are never cool and sophisticated, nor even charmingly eccentric, just weird and pathetic. Not to mention lazy, given that he was still working on his PhD after 6 years...

Yet there is an interesting question: was Griffiths a good criminologist? Does he have a unique insight into serial killers? We'll probably never know, at least not until (or if) the police release some of his writings. But it seems to me that he might have done.

When the average person hears about the crimes of someone like Griffiths, we are not just shocked but confused - it seems incomprehensible. I can understand why someone would want to rob me for my wallet, because I like money too. I can understand how one guy might kill another in a drunken fight, because I've been drunk too. Of course this doesn't mean I condone either crime, but they don't leave me scratching my head; I can see how it happens.

I cannot begin to understand why Griffiths did what he did. My understanding of humanity doesn't cover him. But he is human, so all that really means is that my understanding is limited. Someone understands people like Griffiths, it can't be impossible; but it may be that the only way to understand a serial killer is to be one.

The same may be true of less dramatic mental disorders. Karl Jaspers believed that the hallmark of severe mental illness is symptoms that are impossible to understand: they just exist. I've experienced depression; I've also read an awful lot about it and published academic papers on it. My own illness taught me much more about depression than my reading. Maybe I've been reading the wrong things. I don't think so.

SSRIs and Suicide

Prozac and suicide: what's going on?

Many people think that SSRI antidepressants do indeed cause suicide, and in recent years this idea has gained a huge amount of attention. My opinion is that, well, it's all rather complicated...

At first glance, it seems as though it should be easy to discover the truth. SSRIs are some of the most studied drugs in the world. We have data from several hundred randomized placebo-controlled trials, totaling tens of thousands of patients. Let's just look and see whether people given SSRIs are more likely to die by suicide than people given placebo.

Unfortunately, that doesn't really work. Actual suicides are extremely rare in antidepressant trials. This is partly because most trials only last 4 to 6 weeks, but also because anyone showing evidence of suicidal tendencies is excluded from the studies at the outset. There just aren't enough suicides to be able to study.

What you can do is to look at attempted suicide, and at "suicidality", meaning suicidal thoughts and self-harming behaviours. Suicidality is more common than actual suicide, so it's easier to research. Here's the bad news: the evidence from a huge number of trials is that compared to placebo, antidepressants do raise the risk of suffering suicidality(1) and of suicide attempts(1) (from 1.1 per 1000 to 2.7 per 1000), when given to people with psychiatric disorders.

There's no good evidence that SSRIs are any worse or any better than other antidepressants, or that any one SSRI stands out as particularly bad(1,2). The risk seems to be worst in younger people: compared to placebo, SSRIs raised suicidality in people below age 25, had no effect in most adults, and lowered it in the oldest age groups(1). This is why SSRIs (and all other antidepressants) now carry a "black box" in the USA, warning about the risk of suicide in young people.

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This is very troubling. Hang on though. I mentioned that suicidality is an exclusion criterion from pretty much all antidepressant trials. This is for ethical as well as practical reasons: it's considered unethical to give a suicidal person an experimental drug, and it's really impractical to have patients dying during your trial.

Indeed the recorded rate of suicidality in these trials is incredibly tiny: only 0.5% of the psychiatric patients experienced any suicidal ideation or behaviour at all(1). The other 99.5% never so much as thought about it, apparently. If that were representative of the real world it would be great; unfortunately it isn't. Yet what this all means is that antidepressants could not possibly reduce suicidality in these trials, because there's just nothing there to reduce. Even if, in the real world, they prevent loads of suicides, these trials wouldn't show it.

How do you investigate the effects of drugs "in the real world"? By observational studies - instead of recruiting people for a trial, you just look to see what happens to people who are prescribed a certain drug by their doctor. Observational studies have strengths and weaknesses. They're not placebo controlled, but they can be much larger than trials, and they can study the full spectrum of patients.

Observational studies have found very little evidence suggesting that antidepressants cause suicide. Most strikingly, since 1990 when SSRIs were introduced, antidepressant sales have increased enormously, and the suicide rate has fallen steadily; this is true of all Western countries.

More detailed analyses of antidepressant sales vs. suicide rates across time and location have generally either found either no effect, or a small protective effect, of antidepressant sales(1,2,3, many others). In the past few years, concern over suicidality has led to a fall in antidepressant use in adolescents in many countries: but there is no evidence that this reduced the adolescent suicide rate(1,2).

Another observational approach is to see whether people who have actually died by suicide were taking SSRIs at the time of death. Australian psychiatrists Dudley et al have just published a review of the evidence on this question, and they found that out of a total of 574 adolescent suicide victims from the USA, Britain, and Scandinavia, only 9 (1.5%) were taking an SSRI when they died. In other words, the vast majority of youth suicides occur in non-SSRI users. This sets a very low upper limit on the number of suicides that could be caused by SSRIs.

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So what does all this mean? As I said, it's very controversial, but here's my take, with the standard caveat that I'm just some guy on the internet.

The evidence from randomized controlled trials is clear: SSRIs can cause suicidality, including suicide attempts, in some people, especially people below age 25. The chance of this happening is below 1% according to the trials, but this is still worrying given that lots of people take antidepressants. However, the use of antidepressants on a truly massive scale has not led to any rise in the suicide rate in any age group. This implies that overall, antidepressants prevent at least as many suicides as they cause.

My conclusion is that the clinical trials are not much use when it comes to knowing what will happen to any individual patient. The evidence is that antidepressants could worsen suicidality, or they could reduce it. This is hardly a satisfactory conclusion for people who want neat and tidy answers, but there aren't many of those in psychiatry. For patients, the implication is, boringly, that we should follow the instructions on the packet - be vigilant for suicidality, but don't stop taking them except on a doctor's orders.

Dudley, M., Goldney, R., & Hadzi-Pavlovic, D. (2010). Are adolescents dying by suicide taking SSRI antidepressants? A review of observational studies Australasian Psychiatry, 18 (3), 242-245 DOI: 10.3109/10398561003681319