Monty Python Meets Quackbusting

Over at Crispian Jago's blog, with this work of genius (based on this older work of genius). Geek humour doesn't get much geekier.

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Antidepressants - No Good In Autism?

Children with autism often shown repetitive behaviours, ranging from repeated movements to compulsively collecting or arranging objects and desiring that daily routines are always done in the exact same way. Repetitive behaviour is often considered one of the three core features of autistic disorders (alongside difficulties in social interaction, and difficulties in communication).

SSRI antidepressants are often used to try to treat repetitive behaviours. Unfortunately, they don't work, at least according to a new study - Lack of Efficacy of Citalopram in Children With Autism Spectrum Disorders and High Levels of Repetitive Behavior.

The trial included 149 American children with autism aged from 5 to 17 years old, all of whom had moderate or severe repetitive behaviours. They were randomly assigned to get either citalopram, an SSRI, or placebo, and were followed up for 12 weeks to see if it had any effect on their repetitive behaviours. The dose of citalopram started at 2.5 mg and gradually increased to, in most cases, 20 mg, which is the dose that an adult person with depression would most commonly take - for a kid, this is a high dose.

The results were unequivocal - citalopram had absolutely no benefit over placebo. Zilch. On the other hand, it did cause side effects in some children - gastrointenstinal problems like diarrehea, skin rashes, and, most worryingly, hyperactivity - "increased energy levels", insomnia, "Attention and concentration decreased", and so forth. (Two children in the citalopram group also experienced seizures, but it's not clear that this was related to the drug, as citalopram is not known for causing seizures in adults.)

So, citalopram was not just useless, but actually harmful, in these children. This is the largest trial of an SSRI for repetitive behaviours in autism so far; there have been a few others, including one double-blind study of Prozac finding some benefit, but this is by far the most compelling.

But there's a big question here - why would anyone think that citalopram would work? Citalopram was designed to treat adults with... depression. Hence why it's called an antidepressant. Depression in adults is no more like compulsive behaviour in autistic children than is having a broken leg or heart disease. They're completely different conditions.

The main reason why SSRIs are used to try to treat repetitive behaviour is that they also work quite well against obsessive-compulsive disorder (OCD). People with OCD have repetitive behaviours, "compulsions". They might wash their hands ten times after going to the toilet. Or check that the fridge door is closed and the oven is switched off every time they leave the kitchen. Or count up to one hundred in their head whenever they see the number 13. And so forth.

SSRIs do work against OCD. Does this mean that they ought to also work against the repetitive behaviors in autism? Only if you think all repetitive behaviours are the same, with the same causes.

People with OCD feel compelled to perform their ritualistic behaviours as a way of coping with their "obsessions" - intrusive, unpleasant thoughts that they can't otherwise get out of their heads. Someone might be obsessed with the thought of germs and disease whenever they go to the toilet, and the only way to feel clean is to wash their hands 10 times. They might be obsessed with the idea that their family will die whenever they see the unlucky number 13, unless they "cancel it out" by counting to 100. The repetitive behaviours, in other words, are a consequence of the obsessions, which are unwanted, anxiety-provoking thoughts. SSRIs probably work by making the obsessions seem less troubling, so there is less need for the compulsions.

People with autism are often described as having "obsessions" too, but in the sense of "Things they are very interested in", not "Thoughts they cannot get rid of". Likewise, autistics may show "compulsive behaviours", but not as a way of dealing with obsessions. The words are the same, but the reality is different.

Maybe autistic people just like sameness and routine. That's part of who they are, and it's not something that can be treated with drugs. People with OCD hate having it - they don't like their obsessions or compulsions, they feel stuck with them. The compulsions are a coping mechanism. But in autism, at least most of the time, that's not how it works. An autistic child "compulsively" playing with the same toy over and over, or reading yet another book about their "obsession", dinosaurs, may be perfectly happy. In which case, why give them happy pills? And this is what the authors of the paper eventually suggest -

It may be that the repetitive behavior in children with ASDs is fundamentally different from what is observed among children with obsessive-compulsive disorder in its behavioral picture and in its biologic underpinnings.

Bryan H. King, MD; Eric Hollander, MD; Linmarie Sikich, MD; James T. McCracken, MD; Lawrence Scahill, MSN, PhD; Joel D. Bregman, MD; Craig L. Donnelly, MD; Evdokia Anagnostou, MD; Kimberly Dukes, PhD; Lisa Sullivan, PhD; Deborah Hirtz, MD; Ann Wagner, PhD (2009). Lack of Efficacy of Citalopram in Children With Autism Spectrum Disorders and High Levels of Repetitive Behavior Arch Gen Psychiatry, 66 (6), 583-590

Your Inner Robot

Have you ever stepped onto a stopped escalator? If so, you'll probably have experienced a strange sensation - a rather unique kind of giddy, whole-body jolt - and you may well have stumbled clumsily for a second or so.

But why? And why is it that the phenomenon happens even if you've seen and understood that the escalator is stopped? (This has happened to me, more than once. It's rather disturbing.)

This is the question that prompted Fukui et al, a team of Japanese psychologists, to write a paper wonderfully titled Odd Sensation Induced by Moving-Phantom which Triggers Subconscious Motor Program. As they put it -

This phenomenon raises an intriguing question as to how implicit motor programming escapes from conscious top-down control and offers an opportunity to study it.

Fukui et al took seven men and asked them to walk onto three objects - a moving up-escalator, a stopped up-escalator, and some wooden steps built to be the same size as the escalator steps. The volunteer's movements were analyzed by placing reflective markers onto their back and feet, and recording their movements using an infra-red camera system. They were also asked to rate to what extent they experienced the odd sensation.

The authors point out that there are three possible explanations for the phenomenon -

1. The odd sensation concurrently but independently occurs with the postural or leg behavioral properties [i.e. it has nothing to do with movement and] simple unfamiliarity with encountering a stopped escalator could induce the sensation.
2. The odd sensation occurs due to the unique height of the steps, in which the first step is shorter than others...
3. The odd sensation results from an inappropriate action inconsistent with the current situation despite the proper understanding of the situation. Stepping onto a moving escalator is a highly habituated action, so the habitual motor program for a moving one would emerge even when we step onto a stopped one. The subconscious emergence of the habitual escalator-specific motor program leads to the inappropriate motor behavior, which leads to the odd sensation.

And their results point to the third explanation. The volunteers reported a strong "odd sensation" stepping onto the stopped escalator, but not the equivalent wooden steps. This rules out the possibility that the step height is to blame. Further, walking onto the stopped escalator felt weird even when it was done immediately after two goes on the wooden steps.

The results of the body movement analysis were also enlightening. When you step onto a (moving) up-escalator, you need to walk faster and tilt your body forwards just before you step onto it, in order to maintain balance. And this is what the volunteers did, with the moving escalator. With a stopped escalator, they didn't, which is entirely appropriate. In other words, their movements started perfectly normally.

But when they actually stepped onto the stopped escalator, things suddenly went wrong. Their walking velocity decreased, they swayed forwards, and their feet decelerated too soon on the downward movement - as if they were "expecting" the steps to be higher than they were.

This suggests that, in the stopped-escalator situation, a habitual escalator-specific motor program anticipating the step elevation emerged regardless of the full awareness that the escalator was stopped. The actual downward movement of the heel was therefore too short to arrive at the step, so corrective lower limb movement was required.

The authors interpret these results to mean that the visual stimulus of stepping onto an escalator triggered an escalator-specific movement program, despite the fact that the volunteers consciously knew that this was not required.

The idea of movement program is not new. After all, we all know that when walking, driving, speaking, or doing anything else, a lot of what we do is "unconscious". We're not consciously aware of every single little movement. (At the moment I'm aware of typing, not of moving one finger, then another, then another...) But in this experiment, the movement program was not just unconscious but flew in the face of consciousness - it occurred despite conscious awareness that it was wrong.

But that's not all. The strength of the odd sensation seemed to correlate most strongly with the degree of inappropriate upper-body movement, rather than leg movement. Although this wasn't true in every single subject, and although the mathematics of the correlations are a little complex, the authors make a fascinating suggestion to explain why this is -

[In everyday life] limb movement (e.g., lower limb movement for foot clearance) is controlled by a voluntary component (although an automatic component also exists) with action intention, while posture is controlled mainly in an automatic fashion

In other words, the reason why the automatic-but-wrong leg movements were not felt as "odd" might be that they were felt as part of the conscious act of walking - although of course we know that they can't have really been consciously planned, because the volunteers knew that the escalators were stopped.

But if that's true, and if our minds can trick us in this way, we face the rather mind-bending possibility that a lot of other things we do in life might be only felt to be consciously planned. This is not the first experiment to raise this idea, but it is one of the simplest and most elegant. Philosophers and others with an interest in the question of "free will" should pay close attention next time they step onto an escalator.

Fukui, T., Kimura, T., Kadota, K., Shimojo, S., & Gomi, H. (2009). Odd Sensation Induced by Moving-Phantom which Triggers Subconscious Motor Program PLoS ONE, 4 (6) DOI: 10.1371/journal.pone.0005782

Questioning One in Four: Part 3

Welcome to the third and final post examining the idea that one in four of us suffer mental illness at some point in our lives.

As I explained in parts 1 and 2, "one in four" has no basis in the scientific literature, although given how dubious the literature is, this is not necessarily a bad thing. It's not clear where the one in four meme originally came from, although most of the recent uses probably trace back to a 2001 WHO report which quoted it.

But why has one in four proven so popular? The simple answer is that it's high, but not too high. Were someone to say that one in every two people suffer from mental illness, most of us just wouldn't believe it. That's actually what most published studies have found, but it fails the laugh test. One in four is low enough to be believable but high enough to be striking, attention-grabbing, and memorable.

Why are so many people quoting the highest estimate they can get away with? After all, if we've (unconsciously) decided that one in two is "too high", as we seem to have done, we could equally well decide that one in four is too high. We could redefine "mental illness" such that the prevalence of it was, say, one in ten, or one in fifty. Those would be no more and no less valid than one in four. But we haven't, so why not? There are some obvious, but wrong, explanations -

• Most obvious of all is Big Pharma. It's a well known fact that pharmaceutical companies are pure evil and that Satan sits on the board of directors of most them. And clearly, pharma do have a financial interest here. The more people who are deemed mentally ill, the more who might buy their pills. However, to think that pharma are primarily responsible for the spread of one in four is simplistic. Cynics that we are, no-one takes what pharma says seriously. At the least, they would need some accomplices to help convince people of the idea.
  
• People sometimes accuse governments of talking up prevalence estimates. The Szaszian phrase "the therapeutic state" still crops up, with the implication that the government wants to use mental illness as an excuse to implement authoritarian policies. Well. This conspiracy theory doesn't seem all that realistic, given that the present British government, at least, couldn't conspire to get drunk in a brewery. Indeed if anything, modern governments generally treat the mentally ill as a financial burden. They require often-expensive treatment, and maybe also welfare payments. At least in Britain, the government currently trying to minimize the numbers officially considered mentally ill, to save money.
• Finally, "Psychiatry" is said to be expanding its power by defining everyone as mentally ill. Anyone who has been to a psychiatry conference will find it hard to take the idea of such a grand plot seriously, but more fundamentally, this assumes that psychiatrists like treating people just for the sake of it. Why would they? In some countries, true, they do have a financial incentive to treat as many people as possible, although no more than any other medical professional. But in Britain and other countries with nationalized health-care, psychiatrists are paid a salary and every additional patient is just more work. And more chance of getting called up in the middle of a romantic dinner and having to talk down some suicidal person for three hours.
  

The true explanation, I think, is rather more boring than any of the above. Simply, one in four persists because everyone with an interest in talking about the prevalence of mental illness has an interest in talking it up.

Mental health charities and other advocates for the mentally ill like one in four because it's a great way of fighting the stigma attached to mental illness. One in four represents hard, scientific proof that mental illness is not rare, weird, and freakish - i.e. that the mentally ill are "just like everyone else" and have the same rights. Which is a perfectly good message, and remains one despite the fact that one in four is rubbish.

Academics like one in four - or rather, like high estimates of the prevalence of mental illness - because it gives their work an air of importance. Almost every research paper about depression, for example, starts with a paragraph of formulaic boilerplate to the effect that "Depression is really common". Here's the first paragraph of the first depression paper I plucked from PubMed at random (honestly) -

Major depression is a substantial public health problem, ranking first among the causes of worldwide disability. According to a study by the World Health Organization, depression was estimated as fourth leading cause of disability-adjusted life years (DALYs), a measure of disease burden, in all age groups and the second leading cause in people aged 15–44 years in 2001 (World Health Report, 2001). Lifetime incidence and prevalence estimates are not available for the UK or Scotland (Paykel et al., 2005). The one year prevalence for major depressive disorder (MDD) in Europe has been estimated at 3.9%, 5.0% in women and 2.6% in men (...). A large proportion of these patients remain untreated despite a number of campaigns aiming at increased awareness of depression.

This doesn't quote one in four as such (academics rarely do), but you can see why these authors and everyone else are not exactly lining up to debunk it. I'm not accusing the authors of this paper of being deliberately disingenuous; I'm sure they believe what they wrote. But they wrote it and made it their first paragraph for a reason. It's a running joke in modern science that when you're applying for grant money or trying to get work published, you have to talk up the "practical implications" of your research. In medicine a crucial aspect of this is talking up the seriousness and importance of the disease you're studying.

So, one in four persists because it's in no-one's interest not to say it. There's no conspiracy, just the collective action of various groups all of whom benefit from the idea that mental illness is extremely common. Fascinatingly, the very same mental health charities (and pop psychologists) who are traditionally opposed to academic psychiatry and Big Pharma have ended up promoting statistics which perfectly serve the interests of those groups. Not on purpose, of course. No-one is trying to be deceptive, everyone is just doing what they think is the right thing - but the end result is that this profoundly dubious statistic has become almost universally accepted.

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Questioning One in Four: Part 2

This is the second post in a series examining the idea that one in four people suffer from mental illness at some point in their lives. Those who read the first, and the comments below it, will know that this much-quoted statistic has no apparant basis in the scientific literature. In fact, I'm still not sure where it came from.

But there's more. One in four is a strikingly high figure. That's surely a large part of why it's so widely cited. Yet those studies which have attempted to estimate the lifetime prevalence of mental illness have all arrived at even higher numbers, from 1-in-3 to 2-in-3. 50% is typical. Compared to the actual data, one in four is rather conservative.

But is it really true that half of us suffer from mental illness at some point? Guess.

The 50%+ estimates come from population surveys which attempt to study a random sample of the population of a certain country. In order to establish whether each person is mentally ill or not, they use structured diagnostic interviews. These consists in asking the subject a fixed ("structured") series of questions, and declaring them to have a certain mental disorder if they answer "Yes" to a given number of them.

For example, the National Comorbidity Survey Replication (NCS-R), the most recent American study, used a stuctured diagnostic interview called the NCS-R Interview Schedule, which was based on the DSM-IV criteria for mental illness. You can download the Schedule here. Here's the kind of thing it involves - the possible answers being Yes, Know, Don't Know, or Refuse to Say:

Have you ever in your life had a period lasting several days
or longer when most of the day you felt sad, empty or
depressed?

Have you ever had a period lasting several days or longer when most of the day you were very discouraged about how things were going in your life?

And if you answered yes to these preliminaries, you got some more questions. A lot more:

Think of times lasting two weeks or longer when (this problem/these problems) with your mood (was/were) most severe and frequent. During those times, did your feelings of (sadness/or/discouragement/or/lack of interest) usually last less than one hour a day, between 1 and 3 hours, between 3 and 5 hours, or more than 5 hours?
LESS THAN 1 HOUR..................................1
BETWEEN 1 AND 3 HOURS......................2
BETWEEN 3 AND 5 HOURS......................3
MORE THAN 5 HOURS..............................4
DON’T KNOW.............................................8
REFUSED.....................................................9

And so on. The interviewer's instructions spell out exactly which questions to ask, in which order. They even specify how fast to say certain parts. It's about as close to getting a robot to do the interviewing as technology permits.

Such surveys are nothing if not rigorous - everyone gets asked the same questions. They're usually very large - the NCS-R included 10,000 people. And the diagnoses are well-defined; when the NCS-R talks about "Major Depressive Disorder", we know exactly what it's referring to. These are considerable strengths.

But this impressive diagnostic edifice rests on shaky foundations. For one thing, as Allen Hortwitz and Jerome Wakefield (authors of a flavor-of-the-month book) point out in a provocative article, it is built on the assumption that you can diagnose mental illness purely on the basis of the symptoms. Depression, say, consists in experiencing two weeks or more of sad mood, difficulty sleeping, difficulty concentrating, etc.

Yet this leaves no room for taking into account the context of the symptoms, something that quickly leads to absurd conclusions. Taken literally, the DSM-IV criteria for depression would deem most people to be depressed after a break-up, or even a bad bout of influenza. Of course in real life, no doctor does take them literally (at least, I would hope not.) But this is exactly what population surveys do.

A further problem with this approach is that it relies upon the interviewee to recognise their own psychiatric symptoms - without any training or experience in doing that. Anyone who has suffered from clinical depression will know how it stifles ones ability to take interest or pleasure in activities. And any reasonably experienced clinican, talking to a patient, will be able to recognise this symptom, "anhedonia". You know it when you see it - if you're experienced. But to present a lay person with a yes-no question such as

During the episodes of being sad, empty, or depressed, did you ever lose interest in most things like work, hobbies, and other things you usually enjoy?

And to take their answer as the truth is absurd. Anhedonia is much more than merely losing interest in your work or hobbies; that is a partial description of it, but it no more captures the essence of anhedonia than does the description of music as "a series of notes".

So while Hortwitz and Wakefield argue that population surveys overestimate the prevalence of mental illness, but they might equally well be underestimating it. All it takes is for someone to fail to recognise a certain symptom, and it wouldn't go down on paper. (Imagine asking people, "Are you annoying?" - the most annoying people are annoying precisely because they don't recognise their own annoyingness.) If someone is unwilling or unable to talk about a certain aspect of their lives, it won't get recorded either.

In the case of surveys which attempt to estimate lifetime prevalence, there is also the problem that human memory is not perfect. To ask a 50 year old person whether they have ever had a period lasting 2 weeks or longer when they felt discouraged for over 3 hours per day, and expect a meaningful answer, is - well - bonkers.

So, for all of their strengths, the results of these population surveys could be either overestimating or underestimating the "true" prevalence of mental illness. It seems most likely that they overestimate it, because the estimates are so high that there is little room above them. But equally, everyone in the nation could be secretly hiding immense inner anguish, and these surveys would not pick up on it. The true prevalence might be 100%, for all we know.

And ultimately, the notion of a single "true" estimate for mental illness is the most problematic thing of all. As I suggested in the previous post, you can change the prevalence of mental illness almost at will, simply by declaring some things to not count as mental illnesses. Is drinking too much a mental illness? What about a phobia of heights? What about mild autism? What about problem gambling? What about depression that's not so severe as to prevent people living a normal life? There are no right or wrong answers to these questions. But this means there is no right or wrong value for the prevalence of mental illness.

In the next post, I'll be looking at why the estimate of one in four has proven so popular.

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Horwitz, A., & Wakefield, J. (2006). The epidemic in mental illness: Clinical fact or survey artifact? Contexts, 5 (1), 19-23 DOI: 10.1525/ctx.2006.5.1.19