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The Central Nervous System

The End of the Serotonin Transporter Gene Story?

For over twenty years, there’s been interest in the idea that changes in the serotonin transporter protein might be associated with depression in humans. The hypothesis makes some sense on the face of it, although the entire serotonin/depression connection is a lot more complicated than it’s thought to be in the popular imagination. There’s a polymorphic region (5-HTTLPR) in the gene that codes for the transporter, so it’s tempting to imagine that variations in the tendency towards depressive disorders might correlate with it.

I would not want to try to summarize the literature on this, but it is extensive (that Wikipedia article will give you some idea, as it takes you through the yes-there-is-no-there-isn’t cycle). This new paper, though, is trying to put the question to rest once and for all. Going back over 31 separate data sets, including unpublished ones and totaling over 38,000 patients, the consortium involved finds. . .no evidence for the hypothesis. Even the idea that the polymorphism might only show up as meaningful in life-stress situations takes a hit, since the new analysis suggests that this effect might be so modest and so conditional that it’s essentially of no practical use. This conclusion has been sneaking up on those in the field for some years now, with phrases like “It seems virtually certain that the links between 5-HTTLPR and depression are more complex than previously thoughtappearing frequently.

An awful lot of time and effort has gone into this over the years, and it would appear that the entire thing has been a blind alley. In retrospect, it was a lot to hope for that variations in a single protein could be a linchpin for a complicated human central nervous system condition, and maybe that’s a lesson that everyone can take from this. Higher functions of the human brain, especially whatever it is we’re talking about when we use words like “personality” or “temperament”,  are probably not going to break down to genes so simply, which will certainly come as a disappointment to people writing headlines for magazines and web sites.

23 comments on “The End of the Serotonin Transporter Gene Story?”

  1. luysii says:

    Don’t forget that there are at least 14 different serotonin receptors. Which one/ones are responsible for the therapeutic effect of the SSRIs in depression isn’t known. If it was/they were than a specific agonist might be a useful antidepressant.

    1. Dr CNS says:

      … and don’t forget this is brain research…

      1. luysii says:

        According to Wiki, all but one (5HT_5B) of the 14 are found in the CNS

        1. Dr CNS says:

          Agreed – that’s a fact.
          It is also a fact that our understanding of how the brain works is far from thorough.
          So, maybe we should take this new piece of information and try to build a new hypothesis?

  2. Cameron Beaudreault says:

    MAOIs offered stronger therapeutic potential compared to SSRI’s, although their side effect profile was much greater. Is that area currently a dead end for antidepressant research?

    1. Dolph says:

      Not only MAOIs, also tricyclics are better ADs than SSRIs. And it’s not even close. Heck, are there WORSE ADs than SSRIs? I personally don’t no a single patient who found relieve by using them. SSRIs in my view are the biggest scam in the history of modern drug development.

      1. Emjeff says:

        Wrong – I took fluoxetine for a number of years and it helped me tremendously.

        1. cynical1 says:

          I agree. After retiring from medicinal chemistry, I now run a Mental Health Clinic (no irony there). Many patients as well as their counselors do benefit from SSRIs. No panacea but they have their place. One of our counselors is waltzing around her talking about how great her “happy pill” works. She started a few weeks back. (I won’t take them though……….and I have.)

        2. redfiona says:

          Another happy prozac user here. The difference was remarkable.

  3. Anon says:

    This makes me sad.

    1. Mol Biologist says:

      Serotonin story was ended many years ago with other polymorphism story ( I did my PhD in genetics of human variation). Majority of them have extremely low value diagnostically and therapeutically if you take a look at to 1000 genomes project.
      With a few exceptions to the rules such as prominent example is mutations of the G6PD locus where, if homozygous G6PD enzyme deficiency and consequently Hemolytic anaemia results, but in the heterozygous state are partially protective against malaria. However, as I mentioned before the major player which define genotype/phenotype interaction is genomics background or by simple words what else we have in our genome to supplement it.

  4. Maria says:

    The idea that a single gene might be responsible for Depression was laughable from the start anyway. “Dreaded” Psychology has made the case for parental influence as the main cause long time ago. And thats a big problem, on that front you may not change too much, because the individual brain has already got a certain higher structure. You may not change it at all, that would involve changing complex memories. The desire to find the right “genetic switch” ignores that.

    1. YZARC says:

      No link between a single gene and a CNS disease?????

      1. HTSguy says:

        Example of a single locus with a very strong link to a CNS disease: HTT
        What seems not to exist is a single genetic locus that explains most of the cases of any common neuropsychiatric disease.

        1. Dr CNS says:

          So, maybe the concept of a “link” (correlation?) between a gene and a disease is not that all that actionable?
          Perhaps more “robust” knowledge is needed to pave the way from a gene to a disease?

  5. Mol Biologist says:

    So may be the concept of a target could be replaced with importance of the mechanism? Perhaps for a single locus with a very strong link to a CNS disease: HTT, still no actionable drugs are available!

    1. Dr CNS says:

      yes – I agree. I think the concept of a biological target of drug action is useful, as it is knowing any part of the WHOLE mechanism of action of a drug.
      I also believe there are many other things in operation besides a drug occupying its receptor – most of which we are ignorant of, or are not taking into account seriously.

      1. Big Freddie says:

        Yeah the GWAS and copy number variant story for schizophrenia is literally “these are the regions of the genome where variation can contribute to disease risk”. That is different than finding “the gene” but identifies potential partners in a network involving everything from synaptogenesis to conduction…it is a filter helping at the basic level to characterize the disease…clinical action or drug targets may or may not pop out. We have known “the gene” for cystic fibrosis since 1989–a heck of a lot of protein chemistry had to not only happen but be discovered about this one gene before the first effective drug in 2009…this required “small leaps” in chemistry…the idea that genes gone wrong will lead to quick targets and cures seems odd…I still cant understand NIH and industry hostility to basic science…it is all we have literally for the next few hundred years…sure promise on the horizon etc but without fully known biology everything really is a shot in the dark.. CARts might work for a while…they are a good guess…but the probability of lasting cures seems low given known unkowns and…well you know :-). Anyway…blah blah blah

  6. Todd says:

    I’m curious what this means for the BDNF story for depression then. It’s shown ties to serotonin in the past, but I’m curious if it’s now meaningless or connected to something else.

  7. Mol Biologist says:

    Both cancer and depression also is metabolic disease.
    So, by effective treatment of one condition could help other but do not count on opioids list since they have an opposite mechanism.

    1. loupgarous says:

      Except for tramadol, which inhibits reuptake of serotonin and norepinephrine, and has been reported in the literature to reduce depressive behaviors in chronic pain sufferers.

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