However, tianeptine is serotonin reuptake enhancer and also can help with depression, so any simple deficiency hypothesis also doesn't look good either.
Broadly, the "chemical imbalance" theory, left vague and unspecified, is still basically sane (though not specific enough to be super useful).
>1. Selective serotonin reuptake inhibitors versus placebo in patients with major depressive disorder. A systematic review with meta-analysis and Trial Sequential Analysis. Conclusions: SSRIs might have statistically significant effects on depressive symptoms, but *all trials were at high risk of bias and the clinical significance seems questionable*. SSRIs significantly increase the risk of both serious and non-serious adverse events. The potential small beneficial effects seem to be outweighed by harmful effects.
>2. The trouble with antidepressants: why the evidence overplays benefits and underplays risks. Widespread prescribing has not reduced mental disability or suicide, raising questions about the assessment of evidence on effectiveness and safety of antidepressants
>3. In search of a dose–response relationship in SSRIs—a systematic review, meta-analysis, and network meta-analysis. Conclusions: There is no conclusive level I or level II evidence of a clinically meaningful dose–response relationship of SSRIs as a group or of single substances. High SSRI doses are not recommended as routine treatment.
>4 The serotonin theory of depression: a systematic umbrella review of the evidence "We did not identify *any* trials using ‘active placebo’ or ‘no intervention’ as control interventions. "
[1] https://pubmed.ncbi.nlm.nih.gov/28178949/
[2] https://www.bmj.com/content/370/bmj.m3200
https://www.kcl.ac.uk/news/a-response-to-the-serotonin-theor...
Personally, I both agree that SSRI antidepressants were likely overprescribed early on, and disagree with the notion that the chemical imbalance theory is unsupported. N = 1, they can absolutely work. It took a few to find one that really did, hence I am certain it is not a placebo effect.