A Tale of Two Suppressed Studies

Let me tell you a story. A big, powerful institution commissioned a report into something important. But the authors ended up writing something that the institution’s leaders couldn’t accept. They found it unpalatable. It went against their orthodox dogmas. So, they suppressed it. It never saw the light of day. It’s the report they didn’t want you to read.

Nice story. But does that mean the report is true? Couldn’t they be smarter than the authors of the report? Is “Commissioned to write a report by a big powerful institution” a qualification you would respect in any other context? Maybe they didn’t want you to read the report because it was just a bit rubbish?

The past couple of weeks has seen two classic texts from the ever-popular genre of Suppressed Reports. There was the World Health Organization study on cocaine that concluded that it isn’t all that harmful. And then there was the Environmental Protection Agency report that was sceptical of global warming. They didn’t want you to read either, so we’re told.

I’m not saying these reports are wrong. I haven’t read either. But it’s odd that their "suppression" has granted them the kind of uncritical attention that they would never have had if they’d just been published normally. How many global warming skeptics take what the Environmental Protection Agency says seriously? Yet when they deliberately don’t say something, they’re all ears. It’s like Catholics taking the Pope’s word as infallible, but only when he doesn’t want them to. It’s the argument from authority in reverse.

The Shotgun Approach to Psych Drug Discovery

A foundation is offering to fund research into novel psychiatric medications, we read in the latest Nature Neuroscience:

The Broad Institute in Cambridge, Massachusetts has launched an initiative called ‘PsychHTS’ inviting scientists with ideas and data suggesting novel mechanisms contributing to psychiatric disease to apply for access to the Broad’s infrastructure and expertise for high throughput screening (HTS) of chemical compound libraries.

HTS is a clever technique for discovering new drugs, based on the crude but effective principle of trying hundreds of thousands of different chemicals until you find one which works, by using machines to automatically run the experiments (“assays”) extremely quickly. Hence, “high throughput”. It’s pretty cool.

The Stanley Medical Research Institute wants to use HTS to find new psychiatric drugs. There have been no truly new drugs in psychiatry for a long time: there are dozens of different antidepressants, for example, but they all work (if and when they work) by increasing brain monoamine levels, just like the very first antidepressants, iproniazid and imipramine, discovered in the early 1950s. The same is true of antipsychotics, which all block dopamine D2 receptors, just like the very first, chlorpromazine.

So new drugs for the mind would be great. But how are you going to find them by doing experiments in test-tubes, even if you have 50,000 test-tubes? The mind doesn’t fit in a test-tube. Here’s where the proposal gets a bit iffy:

Readouts may be anything from classical enzymatic reactions ... up to subcellular changes captured by automated high-content imaging. ... ‘Hits’—compounds that affect the assay results in a way that indicates potential usefulness in a psychiatric research context—are automatically retested at several concentrations...

So, the idea is that potential new drugs will be found by measuring how they affect certain cellular processes or chemical pathways. But which ones? Until we know what cellular or protein or enzymatic changes underlie mental illness, we won’t know what to look for. And the whole problem is that we don’t know much about that – if we did we’d have lots of new drugs already.

The article suggests only one route to finding truly novel mechanisms – genetics. In the past few years, there have been many genetic studies trying to find genes which cause mental illnesses. Some of them have identified risk genes which seem to imply new biological pathways. For example, the current orthodoxy is that schizophrenia is caused by abnormalities in the brain’s dopamine system. But the gene most strongly implicated in schizophrenia is called “neuregulin-1”, and it has nothing to do with dopamine. That’s interesting but unfortunately -

Recent genetic studies have indeed suggested new targets, but the identification of specific genetic risk factors remains elusive. The genetic results are themselves variable, often have small effect sizes and need independent replication.

In other words, the genetics evidence is so patchy, that using it as a basis for finding new drugs is like building a house on very shaky foundations. It might stand. But if the genetic links turn out to be spurious, all the subsequent research will have been in vain.

Personally, while I welcome any truly groundbreaking work in psychiatry, I would rather people spend time and money doing better research on the drugs we already have.

Nature Neuroscience Editorial (2009). Mining chemistry for psychiatry Nature Neuroscience, 12 (7), 809-809 DOI: 10.1038/nn0709-809

On Psychiatric Cool

At Somatosphere, "Liz Oloft" (heh) writes about the dilemmas of "coming out" as a user of psychiatric meds while being an academic who researches them: Prozac In The Closet.

Liz is a social scientist, while I'm a card-carrying neuroscientist, but like her I also take antidepressants while studying them, and I identify strongly with her thoughts.

One sentence in particular struck a chord -

Depending on who you ask ... to engage in Lacanian psychoanalysis for neurotic problems of living might be cool, to take an antidepressant for depression without psychotherapy is less cool, and to take a cocktail for bipolar might be even less so (although bipolar disorder may be more legitimate than depression because it seems to be more widely accepted as a “real biological disease”).

This is something which isn't much talked about, but it's absolutely true. Some mental illnesses are just cooler than others. Cool is a famously elusive concept, maybe undefinable. Either you got it or you don't. But some diagnoses certainly have more of it than others. From most cool to least the pecking-order seems to be:

1. "Issues" – problems of living and/or "stress", rather than illness
2. "Physical" conditions with psychiatric symptoms, such as thyroid problems and PMT
3. Anxiety, phobias, panic attacks
4. Substance abuse & addiction
5. Bipolar disorder (manic-depression)
6. Eating disorders
7. Unipolar depression
8. "Personality Disorders"
9. Schizophrenia

This list is, of course, subjective - "cool" inherently is – and it goes without saying that I’m not endorsing this hierarchy, just reporting it as I perceive it. I’m no slave to cool as a glance at my iTunes library would verify.

What does it mean for one thing to be higher on the list than other? Amongst much else it means - that people are more comfortable talking about it and being in the presence of it; that people will tend to prefer it as a diagnosis for themself or a loved-one; and that it's easier to think of "cool" people who have it. And, simply, it means it that it’s easier to “come out” as having it.

Some of the rankings may surprise at first glance. If you read the textbooks, you'd think that bipolar disorder is generally speaking "worse" than unipolar depression. And in many ways it is. But it's still cooler, I think. Cobain sang about "Lithium", the quintessential treatment for mania, not "Imipramine". Hendrix sang "Manic-Depression", not "Depression". Lots of cool, or at any rate famous, people, are bipolar, or are widely believed to be. By contrast, try to think of a famous unipolar depressive, and you'll come up with Winston Churchill with his Black Dog and... who else?

The key factor behind psychiatric coolness seems to be the degree to which a problem is seen as internal to the self. There's little shame in being "stressed" due to things that happen to you, because then the problem is external. You're "normal", it's the situation that's screwed up.

Likewise, as Liz says, bipolar disorder is in an important way cooler than depression, because it's seen a closer to being a "physical” illness that happens to you, like a thyroid problem. That’s as opposed to a weakness or failure of you as a person, which is the most damaging and most persistent stigma of unipolar depression.

The one apparent exception is schizophrenia, which is profoundly stigmatized despite being widely viewed as a biological disease. But isn't this because schizophrenia is seen as a disease that disturbs the self, leaving someone merely "mad" or "insane", no longer responsible for their actions and therefore no longer really a person?

How Far Off Is Mind-Reading?

PopSci.com has a somewhat enthusiastic article about the possibility of using fMRI to "uncover your private thoughts"- Mind-Reading Tech May Not Be Far Off.

Neuroscientists are already able to read some basic thoughts, like whether an individual test subject is looking at a picture of a cat or an image with a specific left or right orientation. They can even read pictures that you're simply imagining in your mind's eye. Even leaders in the field are shocked by how far we've come in our ability to peer into people's minds. Will brain scans of the future be able to tell if a person is lying or telling the truth? ... While we aren't there yet, these possibilities have dramatic social, legal and ethical implications.

But what do we mean by "mind-reading"? I guess what most people mean by the term is being able to tell what someone is thinking, being able to "hear" their private thoughts. A stereotypical fictional "telepath" can get inside their targets minds and tell exactly what's going through them.

Sadly, what most fMRI "mind-reading" experiments have done is rather less impressive. they've shown that it's possible to tell whether someone is thinking about one thing as opposed to a second thing. But only if you already know what both things are, and only if you have already "read" the pattern of neural activity that corresponds to each one.

So, you could scan someone while they are thinking about, say, cats, and then again while they are thinking about dogs. From that, you could work out whether they are thinking about cats or dogs at any given point in time (here's how). If they were thinking about anything else, you'd have no idea what it was, or worse, you'd think it was either a cat or a dog. A lion, for example, would probably activate many of the same pathways that a cat does.

The great majority of "mind-reading" studies are like this. It's still pretty cool, but it's no telepathy. Is there any prospect of true "mind-reading"? In other words, could you read a mental state without knowing what you were looking for in advance?

Maybe. The parts of the brain concerned with visual processing happen to be arranged in a relatively straightforward way,which means that there are predictable relationships between visual stimuli and the areas of the brain that are activated when looking at them. Reports have claimed that it's possible to infer which picture someone is looking at out of a large set (1) and even to reconstruct the image that someone is looking at based purely on the visual cortex activity (2,3). For a good explanation of the last paper, which attracted a lot of attention, see Neurophilosophy.

Such studies come closer to true "mind-reading", but thus far the technique only works with vision. Even assuming that the same areas of the brain light up when you're thinking about something (visual imagery) compared to when you're looking at it (visual perception), the best this method could achieve would be to tell what picture was in someone's head at a given time. In ten years it might be possible to put someone in a scanner and tell, straight off the bat, that they were picturing a small white dog. But if you wanted to know what they were thinking about that dog, you'd be out of luck.

To truly read someone's mind you would need to understand how every brain state relates to every mental state. In other words, you would need to know how the brain allows us to think. At the moment, we really have no ide about that, so true mind-reading remains over the horizon.

Edit: I must be telepathic because I just saw that Mind Hacks covered a new study about mind reading a few hours ago: I know where you are secretly attending! Yet again, it involves the visual cortex.

Are 1 in 64 Kids Autistic?

Quite possibly, yes. In the last post I discussed the interesting background to a new paper about the prevalence of autism in British children, Prevalence of autism-spectrum conditions: UK school-based population study. Here's some more about the study itself.

The authors, Simon Baron-Cohen et al from the University of Cambridge, set out to assess the prevalence of “autistic spectrum conditions” in the county of Cambridgeshire, England, by sampling all of the school children aged 5 to 9 years during 2003-2004.

The most recent major study examining the prevalence of autistic spectrum conditions in Britain was Baird et al (2006), who reported a prevalence of about 1 in 86. But Baron-Cohen et al point out that this may have been too low, since Baird only looked for autism in children who were already on the government's “Special Educational Needs (SEN)” register of children with difficulties in school. If there were autistic children who were doing OK in school, or at least well enough to get by without attracting concern, they’d have been missed.

So, Baron-Cohen’s team first wrote to every school in Cambridgeshire (162 of them) and asked them to report how many of their children had been diagnosed with an autism-spectrum condition. 79 schools replied and reported 83 children diagnosed out of 8824 total, or 1 in 106 children – pretty close to Baird et al's in 2006.

But those were only the kids who had already got a diagnosis. In order to try to find undiagnosed cases, they then sent questionnaires to the parents of 11,635 children. The questionnaires included a screening form developed in Cambridge called the CAST, which asks parents about various aspects of their child’s behaviour (“Does s/he come up to you spontaneously for a chat?” “Does s/he like to do things over and over again, in the same way all the time?” Etc.)

The authors invited all of the kids who scored highly on the CAST to a face-to-face assessment to confirm whether they really had the condition. The end result was that out of 3373 kids whose questionnaires were returned, 11 were judged (in the opinion of the research team) to have an autism-spectrum condition which had never been previously diagnosed.

What does this mean? Well, good question. All it strictly means is that 11 out of 3373 children had undiagnosed autism. However, because not all of the children who scored highly on the CAST agreed to be interviewed, the authors estimate that the true figure was probably more like 22. That compares to 33 out of those 3373 whose parents reported already diagnosed autism. (Actually it was 41 reported, but only an estimated 33 were declared “confirmed”. See page 503 if you’re sceptical of this fudge, but it seems kosher to me.)

The bottom line: for every 3 children with a diagnosis, 2 others went undiagnosed. Since about 1 in 100 children have diagnosed autism, that makes 1 in 64 children with autistic spectrum conditions in total.

But this relies on some assumptions. In particular, this only works if you assume that the parents of autistic children were no more or less likely to complete the CAST questionnaire, and no more or less likely to agree to a face-to-face interview, than parents of the non-autistic kids.

However, it could well be that the parents of autistic children were already concerned that there was “something wrong” with their child and wanted to get a professional opinion, so they were keen to take part – that would mean that this study overestimated the rate of undiagnosed autism. On the other hand, it could equally well be that the autistic children were less likely to get included in the study. Maybe they just didn't want to go along to the interview with a stranger. In which case, the rate of autism would be underestimated.

Because only 29% of parents did the questionnaire and even then only about 60% of the children who scored high came up for the face-to-face, the potential for bias is great. Unfortunately, there is no way of knowing which way the bias operates. The authors acknowledge these concerns and admit that their estimates are not exact.

But this is still an important study. Even if you assume that the data were extremely biased towards finding autistic children there were still 11 cases of undiagnosed autism out of about 11,000 kids aged 5-9, compared to 83 diagnosed, which means that at an absolute minimum 1 in 9 children with autism of that age are undiagnosed. And the true figure is likely to be a lot higher, maybe 2 in 5 as the paper claims.

On this blog I've often been skeptical of claims that mental illness is extremely common. But I can easily believe that 1 in 64 children has a significant autism spectrum-condition, and that some cases go undiagnosed in primary school. While we still don't know the exact numbers, and these will always be somewhat arbitrary since they depend upon the chosen diagnostic, about 1 in 50 sounds about right. Certainly, the idea that autism is an extremely rare condition affecting more like 1 in 2000, as was believed twenty years ago, is out of date.

Baron-Cohen, S., Scott, F., Allison, C., Williams, J., Bolton, P., Matthews, F., & Brayne, C. (2009). Prevalence of autism-spectrum conditions: UK school-based population study The British Journal of Psychiatry, 194 (6), 500-509 DOI: 10.1192/bjp.bp.108.059345

Autism, the Media, and "1 in 58" - the story continues

It was about this time two years ago that my faith in the British media died. It had never been in the best of health, but up until then I believed that the (non-tabloid) newspapers were written by professionals trying to find out and communicate the truth as best they could.

Journalists might be wrong, I thought, but they did their best to ensure that they weren't. And they might have a bad habit of focussing on sensational stories that "sold papers", but such stories would at least be accurate. A career in journalism was something that strongly appealed to me.

What happened on July 8th 2007 was that The Observer printed a front-page article so demented that I’ve never been able to take that newspaper at face value since. And if you can't trust The Observer, which sat on my family's breakfast table every Sunday since before I can remember, you can't trust any of them (at least, I can’t.)

The article was about autism, and it claimed to be a report on a new research study carried out at Cambridge by the famous Professor Simon-Baron-Cohen. The upshot was that Baron-Cohen’s team had found the rate of autism to be 1 in 58 children, much higher than the previous study from a few years earlier, which found a rate of about 1 in 86. Furthermore, The Observer said, two of the team, “world experts” in autism, thought that this “dramatic rise” (i.e. a rise of 50% in a few years!) might be something to do with the much-maligned MMR vaccine.

The original article no longer exists on the Observer’s website, but the WayBack Machine has it.

It was pulled after Ben Goldacre, amongst many others (including Baron-Cohen and even the Government), criticized the piece vociferously and it was, eventually, replaced by an unsatisfactory “clarification”. Goldacre’s take on things was chronicled in a astonishing series of articles (1, 2, 3, 4, et al.) which revealed some horrific journalism, including, amongst much else, attributing opinions to people who didn’t hold them and failing to reveal conflicts of interest. If for some reason you’re not already a Goldacre fan, read those posts, and you’ll see what all of the fuss is about. But you need to know one other thing – he is literally the only journalist in the country who does what he does.

The most damning criticism at the time, however, was that the research in question could not possibly have found an increase in autism rates, let alone a “big surge”, a “dramatic rise”, or an “upward trend”. The new research, quite deliberately, used more extensive assessment criteria than previous studies. It was specifically designed to find the highest possible estimate. So only a fool would try to compare it to other sets of data and see this as evidence of rising rates. Also, even if there had been a real increase, it couldn’t have been because of MMR, because the kids in both studies will have had the MMR vaccine. The oldest kids in the Baird et al study of 9-10 year olds were born in 1991, a few years after MMR was introduced, while the youngest in the Baron-Cohen study were born in 2000, when MMR uptake was, if anything, lower, thanks to the MMR-autism scare.

Now, two years after The Observer’s “scoop”, the research is finally out in the British Journal of Psychiatry: Prevalence of autism-spectrum conditions: UK school-based population study. I’ll be examining this paper in detail in the next post, but here’s what you need to know if you remember the story from 2007:

The paper doesn’t mention the Observer affair but it’s obvious that the authors had the article in mind while they were writing up their results. They repeatedly emphasise that their prevalence estimate cannot be compared to previous ones. They make it very clear (to the point of seeming a bit stilted) that they believe that the apparent rise in prevalence of autism over time is due to better detection and diagnosis, rather than a real “epidemic”. And they do not mention MMR – not that they had any reason to, of course. The highest estimate they arrive at, which they say is probably somewhat too high but close enough, is 1 in 64 children. 1 in 58 doesn’t appear in the paper.

What’s most interesting about the paper is who wrote it. The author list includes Simon Baron-Cohen (obviously) and Fiona Scott. The Observer named Scott as an MMR-autism theorist, something she strongly denied, in 2007. However, fascinatingly, Carol Stott is not an author, although she receives a massive acknowledgement at the end of the paper – “Carol Stott was a member of the research team throughout the main phase of the study and contributed to the coordination and running of the study, data management and data collection. She also made valued contributions to team discussions.” On the basis of this, she clearly had a right to be listed as an author – but wasn’t. We can only assume that she chose not to be, because if the other authors had left her off the list without her permission they would have been guilty of a serious breach of trust.

Carol Stott, you’ll remember, played a role in the Observer autism story. Unlike Fiona Scott, she does (or at least did in 2007) believe that MMR is linked to autism, and she had very close links with Andrew Wakefield as well as displaying a, er, penchant for the scatological in some bizarre emails to journalist Brian Deer. (Goldacre does say he “genuinely warmed to her, and she regrets that many people have fallen into entrenched positions on MMR on both sides” though, so she’s not all bad!)

So, questions remain. How did the preliminary research get leaked in 2007? What happened to make 1 in 58 become 1 in 64? What’s the deal with Stott? We don’t know. But we do know a bit more about autism thanks to this paper, and in the next post I’ll be discussing that.

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On Anonyminity

You'll probably have heard about the "outing" of formerly anonymous blogger Night Jack, a British policeman. Night Jack went to court in an attempt to prevent The Times newspaper from publishing his identity, but the judge ruled against him. His award-winning blog, http://nightjack.wordpress.com/, has been taken down; I don't know if this is going to be permanent.

Lawyer Jack of Kent has a typically lucid and detailed legal commentary on the case, but as a fellow anonymous blogger, I believe that this is an issue which goes beyond British law.

I write anonymously because it allows me to write things that I otherwise couldn't. I could write under my own name, as many excellent bloggers do. However, the content of Neuroskeptic would not be the same.

Broadly speaking, my "neutral" coverage of science news would remain (like this), and my criticism of journalists probably also would (like this). However, I don't feel that my more "critical" writing about science - like this - would be possible without anonymity.

I'm an academic at a junior stage of my career. Some of the targets of my (implicit and explicit) criticism are people and organizations who might well play a part in that career. Quite simply, I don't want to go on record criticizing them, for obvious reasons of self-interest.

Perhaps this just makes me a bit of a coward, but I prefer to think about it in a more philosophical light. Often when we say or write something, two things happen in parallel. We are doing something in the social world, and we are asserting a proposition.

If I were to say to someone "Your wife is having an affair", I would be doing something momentous, something that might well be very painful and damaging. This is why we don't say things like that lightly - even if they are true. We value tact. Yet at the same time, my statement is true (or false), just like any other statement of fact, and it remains true (or false) whether or not I say it.

As a society, we recognize that it's sometimes desirable to allow people to assert things without having to worry about the consequences of their words as a social act. This is why we have anonymous feedback forms, anonymous comment boxes, anonymous witnesses (in some cases). It's also why we don't regard an election as fair and open if it doesn't have a secret ballot.

And in science, we have anonymous peer review. In order for a paper to be published, it must first be subjected to the criticism of one or more experts on the topic in question, writing anonymously. The anonymonity is fundamental because it allows them to criticize the research as harshly as necessary without having to worry about the consequences. Few people want to go on record as criticizing someone else's work, especially as most scientific fields are sufficiently narrow that peer reviewers personally know the authors of most of the papers they have to critique. Yet someone has to do the dirty work of criticism.

So anonymous peer review is valued in science as a way of facilitating objectivity, something otherwise in short supply, because scientists are people with careers and reputations to uphold. At the risk of giving too much dignity to a mere blog, I see Neuroskeptic as a continuation of this review process once papers have been published. Scientific debate shouldn't be hampered by concerns about careers and reputations, although scientists being only human, it is - anonymous comment is one way of getting closer to the ideal of pure objectivity.

All of that said, anonyminity is not all roses. It's open to abuse. Someone could persue a vendetta against a rival by making apparantly objective, anonymous criticisms that were in fact motivated by nothing more than self-interest. This occasionally happens during the process of peer review - a reviewer might trash a manuscript just because they just don't like the results, or because they are planning to publish the same results and they want to do so first. And an anonymous blogger could exploit their status for similar reasons. I would like to think that I have never personally criticized anyone who is acting in good faith, which includes the vast majority of academics. I try to stick to criticising ideas, not people. But of course, I would say that.

So anonymous writing has to be seen for what it is - something that has the potential to be more objective than on-the-record statements, but with no guarantee that it in fact is. Caveat lector, as always.

[BPSDB]

Aripiprazole, Dopamine, and Well-Being - Science or Selling Point?

Suppose you were a drug company, and you've invented a new drug. It's OK, but it's no better than the competition. How do you convince people to buy it?

You need a selling point - something that sets your product apart. Fortunately, with drugs, you have plenty of options. You could look into the pharmacology - the chemistry of how your drug works in the body - and find something unique there. Then, all you need to do is to spin a nice story to explain how the pharmacological properties of your drug make it brilliant.On an entirely unrelated note, aripiprazole (Abilify) is an antipsychotic marketed in the US by Bristol Meyers-Squibb. A Cochrane meta-analysis finds that it's about as good as any other antipsychotic in terms of efficacy and side effects. As good, but no better. However, uniquely, aripiprazole is a D2 receptor partial agonist. Other antipsychotics work by blocking D2 receptors in the brain, switching them off (full antagonism). Aripiprazole also blocks D2 receptors, but it activates them slightly in the process (partial agonism).

Is that a good thing? A paper just published says yes - The relationship between subjective well-being and dopamine D2 receptors in patients treated with a dopamine partial agonist and full antagonist antipsychotics. The research in question was funded, by the way, by Bristol Meyers-Squibb. Let's see if it holds up.

The authors got 22 patients with schizophrenia who were taking an established antipsychotic, either olanzapine or risperidone. These are both D2 antagonists. Incidentally, neither of them is made by Bristol Meyers-Squibb. 11 of the patients were switched to aripiprazole, while 11 stayed on their original drug. There was no blinding, and no randomization. (The dose of aripiprazole was randomized, although still unblinded, but the assignment to aripiprazole itself wasn't).
Lo and behold, the patients who switched reported improved "well-being". Because there was no randomization and no blinding, and because the outcome was entirely subjective, this could be entirely explained as a placebo effect (or an experimental demand effect.) Especially when you consider that the patients were most likely convinced to take part in the study by being told that aripiprazole would make them feel better than their original drug.

That's not all, though. They also did some brain scanning, using PET to measure D2 receptor occupancy. On average aripiprazole blocked more D2 receptors than the other antipsychotics, which is what you'd expect, as it has a very high affinity for that receptor. But it's a partial agonist, remember - it binds to D2 receptors without switching them "off" entirely.

The paper suggests that this is a good thing because it doesn't make people feel horrible, which is what normally happens when you block almost all of someone's D2 receptors (they're rather important). By switching on the receptors as well as blocking them, it makes you feel OK.
Nice story, and scientifically it's not unreasonable. And as you can see on this plot, in the non-aripiprazole patients (triangles), D2 occupancy in the ventral striatum was negatively correlated with well-being, but in the aripiprazole patients (circles), it wasn't.

Great - except that the range of D2 occupancies in the aripiprazole group is so narrow that no correlation would be apparent even if there was one. The occupancies in the aripiprazole group are all extremely high, 80-95%. There's just no room for a correlation to appear. (Think about it this way - in children, age is strongly correlated with height, but if you only looked at a bunch of 7 year olds, you wouldn't know that.) This is high-school statistics.

This scatter-plot is in fact exactly what you'd expect assuming that a) aripiprazole strongly blocks D2 receptors, and makes people feel awful, just like any other strong D2 blocker and b) the placebo effect made some of the aripiprazole group feel (or at least say that they feel) a bit better than they otherwise would.

You'll note also that the aripiprazole group reported feeling no better than the other antipsychotic group, and that the single most miserable patient was on aripiprazole. The paper concludes on an optimistic note -

The present data suggests that aripiprazole may be associated with early and sustained improvement in subjective well-being, notwithstanding the very high D2 occupancy. This may be related to its partial agonist profile at D2 receptors.

I leave it to the reader to evaluate this claim, and to consider how likely we are to progress in our understanding of the brain when so much of the research is funded by organisations with a direct financial interest in certain theories.

[BPSDB]

Mizrahi, R., Mamo, D., Rusjan, P., Graff, A., Houle, S., & Kapur, S. (2009). The relationship between subjective well-being and dopamine D2 receptors in patients treated with a dopamine partial agonist and full antagonist antipsychotics The International Journal of Neuropsychopharmacology, 12 (05) DOI: 10.1017/S1461145709000327

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.

[BPSDB]

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