I am reading about the biology of depression and came across something I can't understand. Here is the thing:

Lesch K-P, et al. (1996) say that people with short alleles of 5-HTTLPR are more prone to anxiety and depression. Pezawas (2005) also say that short allele carriers have worse anterior cingulate cortex - amygdala connectivity, which is observed among MDD patients. This, however, doesn't make much sense to me, since I'd expect people with short allels to have underperforming serotonin transporter - and isn't it overperforming serotonin transporter that contributes to depression by preventing serotonin transmission by sending it back to the presynaptic neuron? So, wouldn't you expect people with long alleles then to be prone to depression more?

To complicate things further, Willeit et al. (2008) do say that enhanced 5-HTT is observed in Depression. And enhanced 5-HTT would be found in people with long 5-HTTLPR?

So my questions are:

  1. Do I understand it right that Willeit's (2008) results contradict Lesch (1996) and Pezawa's (2005) results?
  2. To the best of today's knowledge, is it the people with short or long allels who are more prone to Depression? If the answer is - with short, could you please clear up my confusion about it (see 2d paragraph)?

I hope my question makes sense.


  1. Lesch, K., et al.(1996). Association of Anxiety-Related Traits with a Polymorphism in the Serotonin Transporter Gene Regulatory Region. Science, 274, 1527-1531.
  2. Pezawas, L., et al. (2005). 5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: A genetic susceptibility mechanism for depression. Nature Neuroscience, 8(6), 828-834.
  3. Willeit, M., et al. (2008) Enhanced serotonin transporter function during depression in seasonal affective disorder. Neuropsychopharmacology, (33), 1503-1513

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