The Big Picture
SSRIs flood serotonin globally, which can suppress
dopamine/norepinephrine and blunt mood.
Anti-serotonin strategies (receptor-specific antagonism,
reuptake enhancement, or targeted modulation) often
result in cleaner antidepressant effects with fewer
side effects.
This supports the criticism you mentioned: SSRIs may
“work” only because the brain adapts to the serotonin
disruption, whereas directly reducing or modulating
serotonin is more therapeutic.
The whole 'conversation' is pretty good, and would provide plenty of search terms for helping you figure out what science has actually figured out about depression.
> I've tried 19 antidepressants over about 15 years. Stuck with mirtazapene [...]
Have you tried any anti-serotonin interventions? (chatbot in comment link below)
Mirtazapene is a "tetracyclic antidepressant". I think the development of antidepressants went MAOI -> Tricyclic -> tetracyclic -> SSRI. My chatbot transcript said the SSRI's are marginal drugs, but "SSRIs are much safer in overdose" than the earlier drugs.
My understanding is that the MAOIs were reasonably-effective at bringing people out of an acute depression, but they interacted with high-tyramine foods (fine cheese, etc) to cause high blood pressure. Reversible MAOIs are less problematic than the non-reversible ones. Methylene Blue [MB] is the most ubiquitous of the reversible MAOIs. I felt a definite warming effect with my first MB microdose (a fraction of a milligram), but I've never noticed anything from larger doses.
My comments on this thread might be helpful: https://news.ycombinator.com/item?id=46000812