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DjangoUnhinged t1_iv6efbg wrote

It’s more confirmation, but it’s actually wild how little evidence actually exists - especially in humans - for a serotonergic deficiency in depression. Like there must be some link given the relatively decent efficacy or SSRIs, but the hard evidence is way thinner than most people realize.


tornpentacle t1_iv6hasz wrote

SSRIs tend to have a rather broad binding affinity. Most of them bind not only to serotonin transporters, but also norepinephrine, dopamine, and 2,700 other things to a lesser degree. Especially curious are factors like agonism of the poorly-understood sigma receptors, which now seem heavily implicated in depression, and also the fact that many SSRIs have been demonstrated to affect NGF and/or BDNF, which modulate plasticity. So the action on serotonin may well be completely irrelevant. Since depression is a disorder of the default mode network, wherein (essentially) the channels of communication become so well established that it is very difficult to break free, there is a whole lot of chatter in the research community about how we are all but convinced now that the neuroplastic effects are more responsible for improving depression symptoms than anything to do with serotonin. But there is also a very compelling reason to believe sigma receptors might be involved, because many drugs known to work as rapid antidepressants share sigma agonism in common (and very little/nothing else).


LysergioXandex t1_iv7ng0u wrote

Though the sigma receptors are unusually promiscuous, binding to a wide variety of chemical classes. So sigma receptor activity may just be a shared off-target.


[deleted] t1_iv6iop4 wrote

The vast majority of mental health science has been guesswork and trial and error (at great cost to many who ended up more lab rats than patients).

It’s only the past few years that hard science has really entered the mix and we’re starting to understand how and why things work