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.

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.

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.


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.


ResearchBlogging.orgMizrahi, 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

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.
ResearchBlogging.orgBryan 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

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