Wednesday, 10 April 2013

Anxious Times

I’ve been intending to write this piece for a while, but I have to confess to some trepidation. I started working in anxiety genetics in October, knowing that it was somewhat of a backwater compared to spearhead fields such as schizophrenia. It’s not that no-one cares about anxiety – there are some incredibly clever people working in the field – but there is a definite feeling that it is understudied. With this in mind, it was with some reticence that I told people what I was to do in my PhD. To my surprise, nearly everyone I’ve spoken to, from those who’ve known me since before I was born, to the drunk woman singing Les Miserables on the train, has responded incredibly positively; folk really think anxiety is important, and the value of improving treatments of the disorder is seemingly obvious.

Which is wonderful. Obviously. I mean, anxiety IS important, and improving treatment will benefit a hell of a lot of people. It’s just… I need to actually understand it now! I’m not a psychologist by any means but if I’m going to really sell my stuff to the world at large (which is the whole point of science, as far as I’m concerned, and arguably one of the things it does least well), then I have to be able to offer insight on the disorder.

One thing I can try to explain is why anxiety is understudied, and why it’s probably always going to be a challenge. Historically, work in psychiatry tended to focus on studies using inpatients of psychiatric hospitals; to be blunt, such patients tended to be those separated from society out of fear, and hence the dominance of schizophrenia and bipolar disorder. In comparison, anxiety and depression, though widespread, are viewed as much more normative; tell someone you refused to fly because you’re scared of planes, and they’ll regale you with their own ‘quirky’ fears; tell them you don’t like to fly because the plane talks to you while you’re trying to sleep, and they’ll back away… slowly.

The divide still exists, and it is likely to remain. As psychiatric genetics has progressed to the current trend for genome-wide studies of association (basically “is this bit of DNA found in patients more often than in non-patients?), it has become clear that most psychiatric disorders have complex causation at a genetic level. However, anxiety and depression may be the most complex of the lot. In schizophrenia, there are now tens of genetic variants that have cropped up in multiple studies, and which we can be relatively confident are playing a role in predisposing their carriers to developing the disorder (quite how they are doing this is an entirely different kettle of fish, or possibly a lake of whale sharks). In depression, no finding has proved consistent. Not a one; and that’s taking into account a lot of data being analysed by the best minds in the business. The story is likely to be the same for anxiety, although that’s not clear because the necessary study size just hasn’t been reached yet.

Therein lies a crucial point; anxiety and depression are common – the chances are you know multiple people who’ve suffered, or are suffering from one or the other. Why, then, are the sample sizes not big enough to make firm conclusions?. You could say that the question is a silly one, that there’s no such thing as a big enough sample size, that bigger is always better (I’ll avoid the crude sexual pun, not least because there’s the suggestion it’s untrue - Paper abstract (aptly enough from PNAS)). You’d be quite right; we can make a conclusion from the study sizes we’ve got, and it is that none of the bits of DNA we’ve looked at has a big enough effect to be greater than chance in the samples we’ve used. This is one probable reason why anxiety and depression genetics has had fewer positive results than schizophrenia genetics; the relevant genes have smaller effects.

There is another problem; there’s too much variation. Anxiety and depression can be categorised into a plethora of different forms, and even within those forms two presentations might involve quite different symptoms and require diverse approaches to treat. This is a general issue of psychiatry (and arguably of medicine), but it does appear to affect anxiety and depression rather a lot . It’s also a big sticking point for the studies being done. If the patient group being looked at is made up not of one disorder, but of several sub-disorders, each sub-disorder may have specific genetic bases, and, because they are all mixed together, none of them can be found. Imagine you have two baskets, and two sets of balls with slightly different colours. If you have equal numbers of balls, and you separate them such that almost all the lighter balls are in one basket, it is easy to split the baskets. If you only have a few lighter balls, however, it becomes very difficult to tell the baskets apart; without examining every ball, the baskets look essentially identical. That, in a nutshell, is the current situation for anxiety and depression genetics. They’re a load of balls.        

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