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Chapter 2: Short genes are involved other mental health problems too
Revised 6/2006
Summary: In Chapter 1, we looked at the effects of the short version of the serotonin transporter gene on depression risk. Inheriting two short versions ("alleles") is associated with much higher rates of depression than seen in people with two long versions. However, it appears that inheriting two short alleles is associated with other differences in mental health as well.
People with "two shorts" -- the "Blue People" from Chapter 1 -- are more reactive to fearful stimuli: their brain's fear center, the amygdala, becomes more active than that of people with "two longs". Secondly, it appears (this is not as well established quite yet, in humans at least) that individuals with "two shorts" are more likely to consume large amounts of alcohol; but, according to one study just published, only if they also had a stressful childhood.
Acknowledgement: In this chapter we see the work of Dr. Ahmad Hariri and colleagues.
There are two separate stories here, each involving the Serotonin Transporter gene discussed in chapter 1. First we'll look at the effect of inheriting "two shorts" on how people respond to fearful expressions. Then we'll look at the effect on how people respond to antidepressant medications.
Fear
Research clearly shows that human fear responses, such as when you see someone who is in a position to hurt you frown in anger, are controlled in some way by a part of the brain called the amygdala. You can learn about the location of the amygdala in the human brain using the Brain Tour about fear.
In the important work of Dr. Hariri, when he was at the NIMH with Dr. Weinberger, research subjects were asked to look at the following image while their brains were monitored in a PET scanner:
Which of the three faces is unlike the other two? Answering this question focuses your attention on the fear in this woman's expression, right? Imagine what your brain is doing while you look at those expressions. This includes just looking at images and trying to figure out which one is different, right? That's what your brain is doing when you look at the following picture, following the same instructions (which of the three is different from the other two?):
Now, imagine you could "subtract" the activity of your brain just processing images of ovals, from the activity processing faces. The difference between the two is related to the facial images themselves, in this case primarily the emotion of fear. Dr. Hariri and his colleagues did this subtraction and found the following difference in brain activity. On the left are people with one or two short serotonin transporter alleles; on the right are people with two longs:
It may not look very impressive, the slightly more prominent redness and area on the left, versus the right. But the raw numbers look a bit more impressive, I think:
Comparing to the "two longs" group on the left (the L group), you can see that there was more brain activation caused by fear-images in the amygdalae of the subjects with "one or two shorts", the S group on the right.
Like the story from Dr. Caspi and the New Zealand research team (Chapter 1), this work also was published in Science, because of the implications of the results as well as the precision of the research.
Isn't it tempting to try to connect the work of these research groups? How do greater reactions from the amygdala relate to the greater frequency of depression in the short-allele people?
Update 6/2006:
The connection between this gene length difference and mental health problems is
strengthening. Indeed, the gene differences have been shown to influence how
well people respond to treatment. Just as you might predict, people
with two shorts did not respond as well to an antidepressant (SRI) for treatment
of panic disorder,Perna
bulimia,Monteleone
or social phobia.Stein
What about depression? Wouldn't you think that having two shorts would also affect response to an antidepressant there too? It appears likely that this is also true: several studies have already shown that people with two shorts do not respond as well to antidepressant treatment. But as reviewed in 2004, Malhotra a few studies have not found this result, including one in Korea, suggesting that there may be an ethnic difference or other factors which may need to be taken into account. Perhaps one of those factors might be childhood trauma, as shown in the original study about yellow people and blue people (Chapter 1), where the difference in depression only showed up when combined with a rough childhood.
Ideally we could use this kind of information to choose treatments most effective for a particular person's genetic makeup. So far that's still out of reach: the studies referred to here show general differences, not accurate predictors of treatment response. The results described here are not consistent enough to say "Oh, you have two longs? You'll do well on this medication"; or "You have two shorts? You'd do better to start with this treatment approach".
I'll try to keep this section updated as more research in this area emerges.