I believe the only thing we are pretty sure about is that we don't know why SSRIs work. What we believe we know is that low serotonin in the brain does not dir

I believe the only thing we are pretty sure about is that we don't know why SSRIs work. What we believe we know is that low serotonin in the brain does not directly cause depression, and artificially lowering serotonin in individuals does not induce depression (at least not in the way researchers have done so, within the time limits they measured). None of this necessarily means that SSRI activity downregulating the reuptake of serotonin is not the primary mechanism of action (pharmacologically speaking, it definitely is the main thing this class of drug is doing in the body). It's worth noting that we also have a ton of serotonin receptors in our GI tract, and SSRIs do have notable activity there as well, to the point that they can relieve chronic constipation in some individuals. Although levels of serotonin outside the brain (which represent 95% of serotonin produced by the body and our microbes) generally get ignored in analysis of depression, since serotonin cannot cross the blood brain barrier, it may well be very relevant to human health, both physical and mental, for as yet unknown reasons.