Dear all,

First: I know that the Serotonin hypothesis of depression has been questioned (https://www.nature.com/articles/s41380-022-01661-0). But I am trying to understand the logic between some "findings" for my lectures.

I read that depressed people often have two short alleles of the 5-HTTLPR gene,´.

5-HTTLPR relates to serotonin reputable proteins. As far as I understood, two short alleles lead to less serotonin re-uptake.

(https://www.cambridge.org/core/journals/the-british-journal-of-psychiatry/article/stressful-life-events-5htt-genotype-and-risk-of-depression/A7DBD1B9F9743C94BE69C6A8AE8B0A40)

But now I do not really understand how this links to depression:

If the re-uptake is limited, shouldn't that lead to more serotonin in the cleft?

How are SSRIs successful in treating depression, if they already have less uptake and the SSRIs reduce it even further?

Would be great if you could help me to get my head around this.

Thanks so much,

Kat