Clever New Scheme

CNS Response are a California-based company who offer a high-tech new approach to the personalized treatment of depression: "referenced EEG" (rEEG).

This is not to be confused with qEEG, which I have written about previously. What is rEEG? It involves taking an EEG recording of resting brain activity and sending it - along with a cheque, naturally - to CNS Response, who compare it to their database of over 1,800 psychiatric patients who likewise had EEGs taken before they started on various drugs. They look to see which drugs worked best in people with an EEG profile similar to yours, and give you a fancy report with their recommendations.

That's not completely implausible. It could work. Does it? CNS Response and some academic collaborators have just published a paper saying yes: The use of referenced-EEG (rEEG) in assisting medication selection for the treatment of depression. How solid is it? Well, it would be wrong to say that there are many problems with this study. But then if you run off a cliff and plummet into a volcano, you've only made one mistake.

Depressed patients were randomized to one of two groups: treatment-as-usual, which generally meant the common antidepressants bupropion, citalopram, or venlafaxine, vs. rEEG-guided personalized drug treatment. The trial was pretty large, with 114 patients randomized, and pretty long, 12 weeks. The patients had failed to respond to at least one antidepressant (mean: 1.5) during the current episode, so they were slightly "treatment-resistant", though not extremely so.

What happened? The rEEG-guided group did better on the QIDS16SR self-report scale, and on most other measures. Not enormously: take a look at the graph, notice that the vertical axis doesn't start at zero. But better.
Great, they did better. But why? The problem with this study is that the rEEG-guided group got a very different set of drugs to the control group. No less than 55% of them got stimulants, either methylphenidate (Ritalin) and dexamphetamine (speed). These drugs make you feel good. That's why they're illegal, that's why people pay good money for them on the street.

It's debatable whether stimulants are clinically useful as antidepressants in the long term, but they've got a good chance of making you feel nice for a few weeks, and make you say you feel better on a rating scale. Plus there's nothing like a pep pill to drive active placebo effects.

The authors say that "Almost all of the studies with depression not associated with medical disorders have reported minimal or no antidepressant effect of stimulants", and refer to some 1980s studies - yet their own trial has just shown that they do work in more than 50% of patients, and the latest Cochrane meta-analysis finds stimulants do work in the short term...

The other big names in the EEG group were MAOis (selegiline or tranylcypromine). These are often effective in treatment-resistant depression. Not necessarily more so than other drugs, but remember that these patients had already failed at least one SSRI(*). Yet the control group were, it seems, almost all given SSRIs - either citalopram, or venlafaxine, which is effectively an SSRI at low doses, e.g. the average dose used here, 141 mg. (It does other stuff, but only at higher doses of 225 mg or 300 mg.)

In summary, there were two groups in this trial and they got entirely different sets of drugs. One group also got rEEG-based treatment personalization. That group did better, but that might have nothing to do with the rEEG: they might have done equally well if they'd just been assigned to stimulants or MAOis etc. by flipping a coin. We cannot tell, from these data, whether rEEG offered any benefits at all.

What's curious is that it would have been very simple to avoid this issue. Just give everyone rEEG, but shuffle the assignments in the control group, so that everyone was guided by someone else's EEG. So you'd give control Patient 2 the drugs that Patient 1 should have got, and vice versa; swap 3 and 4, 5 and 6, etc.

This would be a genuinely controlled test of the personalized rEEG system, because both groups would get the same kinds of drugs. It would have been a lot easier too. For one thing it wouldn't require the additional step of deciding what drugs to give the control group. The authors decided to follow the STAR*D treatment protocol in this study, which is not unreasonable, but that must have been a bit of a hard decision.

Second, it would allow the trial to be double-blind: in this study the investigators knew which group people were in, because it was obvious from the drug choice. Thirdly, it wouldn't have meant they had to exclude people whose rEEG recommended they get the same treatment that they would have got in the control group... and so on.

Hmm. Mysterious. Anyway, we may be hearing more about CNS Response soon, so watch this space.

(*) - Technically, some of them had failed an SSRI and some had failed "2 or more classes of antidepressants", but one of those classes will almost certainly have been an SSRI, because they're the first-line treatment.

ResearchBlogging.orgDeBattista, C., Kinrys, G., Hoffman, D., Goldstein, C., Zajecka, J., Kocsis, J., Teicher, M., Potkin, S., Preda, A., & Multani, G. (2010). The use of referenced-EEG (rEEG) in assisting medication selection for the treatment of depression Journal of Psychiatric Research DOI: 10.1016/j.jpsychires.2010.05.009

Autism And Wealth

We live in societies where some people are richer than others - though the extent of wealth inequality varies greatly around the world.

In general, it's sad but true that poor people suffer more diseases. Within a given country almost all physical and mental illnesses are more common amongst the poor, although this isn't always true between countries.

So if a certain disease is more common in rich people within a country, that's big news because it suggests that something unusual is going on. Autism spectrum disorders (ASDs) have long been known to show this pattern, at least in some countries, but this has often been thought to be a product of diagnostic ascertainment bias. Maybe richer and better-educated parents are more likely to have access to services that can diagnose autism. This is a serious issue because autism often goes undiagnosed and diagnosis is rarely clear-cut.

An important new PLoS paper from Wisconsin's Durkin et al suggests that, while ascertainment bias does happen, it doesn't explain the whole effect in the USA: richer American families really do have more autism than poorer ones. The authors made use of the ADDM Network which covers about 550,000 8 year old children from several sites across the USA. (This paper also blogged about here at C6-H12-O6 blog.)

ADDM attempts to count the number of children with autism based on

abstracted data from records of multiple educational and medical sources to determine the number of children who appear to meet the ASD case definition, regardless of pre-existing diagnosis. Clinicians determine whether the ASD case definition is met by reviewing a compiled record of all relevant abstracted data.
Basically, this allowed them to detect autism even in kids who haven't got a formal diagnosis, based on reports of behavioural problems at school etc indicative of autism. Clearly, this is going to underestimate autism somewhat, because some autistic kids do well at school and don't cause any alarm bells, but it has the advantage of reducing ascertainment bias.

What happened? The overall prevalence of autism was 0.6%. This is a lot lower than recent estimates in 5-9 year olds in the UK (1.5%), but the UK estimates used an even more detailed screening technique which was less likely to leave kids undetected.

The headline result: autism was more common in kids of richer parents. This held true within all ethnic groups: richer African-American or Hispanic parents were more likely to have autistic children compared to poorer people of the same ethnicity. So it wasn't a product of ethnic disparities.

Crucially, the pattern held true in children who had never been diagnosed with autism, although the effects of wealth were quite a bit smaller:

The difference in the slope of the two lines suggests that there is some ascertainment bias, with richer parents being more likely to get a diagnosis for their children, but this can't explain the whole story. There really is a correlation with wealth.

So what does this mean? This is a correlation - the causality remains to be determined. There are two obvious possibilities: to put it bluntly, either being rich makes your kids autistic, or having autistic kids makes you rich.

How could being rich make your children autistic? There could be many reasons, but a big one is paternal age: it's known that the risk of autism rises with the age of the father, maybe because the sperm of older men accumulates more genetic damage, and this damage can cause autism. In general richer people wait longer to have kids (I think, although I can't actually find the data on this) so maybe that's the cause.

How could having autistic kids make you richer? Well, unfortunately I don't think it does directly, but maybe being the kind of person who is likely to have an autistic child could. Autism is highly heritable, so the parents of autistic children are likely to carry some "autism genes". These could give them autistic traits, or indeed autism, and autistic traits, like being intensely interested in complex intellectual matters, can be a positive advantage in many relatively well paid professions like scientific research, or computing. Marginal Revolution's Tyler Cowen recently wrote a book all about that. I hope I will not offend too many when I say that in my experience it's rare to meet a scientist, IT person or, say, neuroscience blogger, who doesn't have a few...

ResearchBlogging.orgDurkin, M., Maenner, M., Meaney, F., Levy, S., DiGuiseppi, C., Nicholas, J., Kirby, R., Pinto-Martin, J., & Schieve, L. (2010). Socioeconomic Inequality in the Prevalence of Autism Spectrum Disorder: Evidence from a U.S. Cross-Sectional Study PLoS ONE, 5 (7) DOI: 10.1371/journal.pone.0011551

I Feel X, Therefore Y

I'm reading Le Rouge et le Noir ("The Red and the Black"), an 1830 French novel by Stendhal...

One passage in particular struck me. Stendhal is describing two characters who are falling in love (mostly); both are young, have lived all their lives in a backwater provincial town, and neither has been well educated.

In Paris, the nature of [her] attitude towards [him] would have very quickly become plain - but in Paris, love is an offspring of the novels. In three or four such novels, or even in a couplet or two of the kind of song they sing at the Gymnase, the young tutor and his shy mistress would have found a clear explanation of their relations with each other. Novels would have traced out a part for them to play, given them a model to imitate.
The idea that reading novels could change the way people fall in love might strange today, but remember that in 1830 the novel as we know it was still a fairly new invention, and was seen in conservative quarters as potentially dangerous. Stendhal was of course pro-novels (he was a novelist), but he accepts that they have a profound effect on the minds of readers.

Notice that his claim is not that novels create entirely new emotions. The two characters had feelings for each other despite never having read any. Novels suggest roles to play and models to follow: in other words, they provide interpretations as to what emotions mean and expectations as to what behaviours they lead to. You feel that, therefore you'll do this.

This bears on many things that I've written about recently. Take the active placebo phenomenon. This refers to cases in which a drug creates certain feelings, and the user interprets these feelings as meaning that "the drug is working", so they expect to improve, which leads them to feel better and behave as if they are getting better.

As I said at the time, active placebos are most often discussed in terms of drug side effects creating the expectation of improvement, but the same thing also happens with real drug effects. Valium (diazepam) produces a sensation of relaxation and reduces anxiety as a direct pharmacological effect but if someone takes it expecting to feel better, this will also drive improvement via expectation: the Valium is working, I can cope with this.

The same process can be harmful, though, and this may be even more common. The cognitive-behavioural theory of recurrent panic attacks is that they're caused by vicious cycles of feelings and expectations. Suppose someone feels a bit anxious, or notices their heart is racing a little. They could interpret that in various ways. They might write it off and ignore it, but they might conclude that they're about to have a panic attack.

If so, that's understandably going to make them more anxious, because panic is horrible. Anxiety causes adrenaline released, the heart beats ever faster etc., and this causes yet more anxiety until a full-blown panic attack occurs. The more often this happens, the more they come to fear even minor symptoms of physical arousal because they expect to suffer panic. Cognitive behavioural therapy for panic generally consists of breaking the cycle by changing interpretations, and by gradual exposure to physical symptoms and "panic-inducing" situations until they no longer cause the expectation of panic.

This also harks back to Ethan Watters' book Crazy Like Us which I praised a few months back. Watters argued that much mental illness is shaped by culture in the following way: culture tells us what to expect and how people behave when they feel distressed in certain ways, and thus channels distress into recognizable "syndromes" - a part to play, a model to imitate, though probably quite unconsciously. The most common syndromes in Western culture can be found in the DSM-IV, but this doesn't mean that they exist in the rest of the world.

Like Stendhal's, this theory does not attempt to explain everything - it assumes that there are fundamental feelings of distress - and I do not think that it explains the core symptoms of severe mental illness such as bipolar disorder and schizophrenia. But people with bipolar and schizophrenia have interpretations and expectations just like everyone else, and these may be very important in determining long-term prognosis. If you expect to be ill forever and never have a normal life, you probably won't.

The World Turned Upside Down

This map is not “upside down”. It looks that way to us; the sense that north is up is a deeply ingrained one. It's grim up north, Dixie is away down south. Yet this is pure convention. The earth is a sphere in space. It has a north and a south, but no up and down.

There’s a famous experiment involving four guys and a door. An unsuspecting test subject is lured into a conversation with a stranger, actually a psychologist. After a few moments, two people appear carrying a large door, and they walk right between the subject and the experimenter.

Behind the door, the experimenter swaps places with one of the door carriers, who may be quite different in voice and appearance. Most subjects don't notice the swap. Perception is lazy: whenever it can get away with it, it merely tells us that things are as we expect, rather than actually showing us stuff. We often do not really perceive things at all. Did the subject really see the first guy? The second? Either?

The inverted map makes us actually see the Earth's geography, rather than just showing us the expected "countries" and "continents". I was struck by how parochial Europe is – the whole place is little more than a frayed end of the vast Eurasian landmass, no more impressive than the one at the other end, Russia's Chukotski. Africa dominates the scene: it can no longer be written off as that poor place at the bottom.

One of the most common observations in psychotherapy of people with depression or anxiety is that they hold themselves to impossibly high standards, although they have a perfectly sensible evaluation of everyone else. Their own failures are catastrophic; other people's are minor setbacks. Other people's successes are well-deserved triumphs; their own are never good enough, flukes, they don't count.

The first step in challenging these unhelpful patterns of thought is to simply point out the double-standard: why are you such a perfectionist about yourself, when you're not when it comes to other people? The idea being to help people to think about themselves in more like healthy way they already think about others. Turn the map of yourself upside down - what do you actually see?


How many fingers do you have?

10, obviously, unless you've been the victim of an accident or a birth defect. Everyone knows that. You count up to ten on your fingers, for one thing.

But look at your left hand - how many fingers are on it? Little finger, ring finger, middle finger, first finger... thumb. So that's 4. But then we'd only have 8 fingers, and we all know we have 10. Unless the thumb is a finger, but is it?

Hmm. Hard to say. Wikipedia has some interesting facts about this question, and on Google if you start to type in "is the thumb", the top suggested search terms are all about this issue. It's a tricky one. People don't seem to know for sure.

But does that mean there's any real mystery about the thumb? No - we understand it as well as any other part of the body. We know all about the bones and muscles and joints and nerves of the thumb, we know how it works, what it does, even its evolutionary history (see The Panda's Thumb by Steven J Gould, still one of the greatest popular science books ever.) Science has got thumbs covered.

The mystery is in the English language, which isn't quite clear on whether the word "finger" encompasses the human thumb; for some purposes it does, i.e. we have 10 fingers, but for other purposes it probably doesn't, although even English speakers seem to be in two minds about the details (see Google, above).

Notice that although the messiness seems to focus on the thumb, the word "thumb" is perfectly clear. The ambiguity is rather in the word "finger", which can mean either any of the digits of the hand, or, the digits of the hand with three joints. Take a look at your hand again and you'll notice that your thumb lacks a joint compared to the fingers; something I must admit I'd forgotten until Wikipedia reminded me.

Yet it would be very easy to blame the thumb for the confusion. After all, the other 4 fingers are definitely fingers. The fingers are playing by the rules. Only the thumb is a troublemaker. So it comes as somewhat of a surprise to realize that it's the fingers, not the thumb, that are the problem.


So words or phrases can be ambiguous, and when they are, they can lead to confusion, but not always in the places you'd expect. Specifically, the confusion seems to occur at the borderlines, the edge cases, of the ambiguous terminology, but the ambiguity is really in the terminology itself, not the edge cases. To resolve the confusion you need to clarify the terminology, and not get bogged down in wondering whether this or that thing is or isn't covered by the term.

It's important to bear in this in mind when thinking about psychiatry, because psychiatry has an awful lot of confusion, and a lot of it can be traced back to ambiguous terms. Take, for example, the question of whether X "is a mental illness". Is addiction a mental illness, or a choice? Is mild depression a mental illness, or a normal part of life? Is PTSD a mental illness, or a normal reaction to extreme events? Is... I could go on all day.

The point is that you will never be able to answer these questions until you stop focussing on the particular case and first ask, what do I mean by mental illness? If you can come up with a single, satisfactory definition of mental illness, all the edge cases will become obvious. But at present, I don't think anyone really knows what they mean by this term. I know I don't, which is why I try to avoid using it, but often I do still use it because it seems to be the most fitting phrase.

It might seem paradoxical to use a word without really knowing what it means, but it isn't, because being able to use a word is procedural knowledge, like riding a bike. The problem is that many of our words have confusion built-in, because they're ambiguous. We can all use them, but that means we're all risking confusing each other, and ourselves. When this gets serious enough the only solution is to stop using the offending word and create new, unambiguous ones. With "finger", it's hardly a matter of life or death. With "mental illness", however, it is.

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