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