You haven't actually cited anything about SSRIs inducing appreciable apoptosis in healthy neuronal cells or degeneration in vivo - all the papers cited concern cancer cell lines or yeast, and the yeast cells were given micromolar concentrations of an SSRI apparently.
If you look back at what I copy and pasted for you earlier, the authors of one paper even acknowledge that the selectivity of SSRIs inducing appreciable apoptosis only in cancerous cells is actually desirable in terms of using SSRIs for cancer -
"Assessment of paroxetine cytotoxicity in primary mouse brain and neuronal cultures showed significantly lower sensitivity to the drug's proapoptotic activity.
The high sensitivity to these drugs of the cancer cell, compared with primary brain tissue, suggests the potential use of these agents in the treatment of brain-derived tumors."
But at the end of the day I don't really know where you are going with all this? There are many ways by which SSRIs could cause persisting adverse and detrimental effects, especially in people who are already diseased. I wouldn't tunnel vision on programmed cell death.
For example, one of the concerns with chronic benzo use leading to dementia is that benzos impair REM sleep - SSRIs impair REM sleep as well, so there could be some concern there. There are even concerns that anticholinergics speed along neurodegenerative disease in the elderly, and this could be due to increased accumulation of plaques.
When we are talking about neurodegenerative disease, you have to think
much larger than the cell culture, and you also have to consider that the diseases the meds are hoping to treat might also predispose one to developing neurodegenerative disease and this adds a lot more confounders to the situation.
Obviously these studies are difficult to do because there are some many confounders, but here is an example
https://www.researchgate.net/public...a_in_patients_with_severe_depressive_disorder
"It was concluded that continued long-term treatment with older antidepressants is associated with a
reduced rate of dementia in patients treated in psychiatric healthcare settings, whereas continued treatment with other kinds of antidepressants is not."
My point is that
regardless of whether TCA's show apoptotic activity in vitro, their in vivo effects on the risk of developing neurodegenerative disease could be completely different.
Moreover, even if there is some evidence that SSRIs increase the risk of neurodegenerative disease (which there is), it would be difficult to link this to a direct action of SSRIs on cells that induced apoptosis rather than something like chronically impaired REM.
RE: fetus vs. adult
There could be some advantages to restoring plasticity to that of a younger brain in some cells. For example see the following
"
Critical period plasticity in the mammalian visual cortex is a well-characterized model for cortical development and plasticity [37,38,87,88] (Figure 3). It is widely thought that similar processes govern the development and tuning of neuronal connectivity in other cortical areas as well [1,88]. Recent studies have revealed that critical period-like plasticity can be reactivated in the adult visual cortex by a number of treatments, including enrichment and chronic fluoxetine treatment (Figure 3D) [40,48,59,62,89,90].
Reactivation of developmental plasticity in adult brain is apparently not restricted to the visual cortex. Chronic fluoxetine treatment induces a dematuration of neurons in the mouse DG that extends to the already matured granule neurons [58]. A recent study used the fear-conditioning paradigm to show that chronic fluoxetine treatment increases neuronal plasticity in the amygdala and leads to the long-term removal of conditioned fear response when fluoxetine treatment is combined with extinction training; neither fluoxetine treatment nor extinction training alone produced a long-term fear removal [60].
These findings demonstrate that enriched environment or fluoxetine treatment in adult animals reactivates a critical period-like plasticity, which facilitates the reorganization and functional recovery of a network miswired during development.
In addition to synapse number, synaptic strength is also dynamically regulated by environmental experiences, including enriched environment, exercise, and antidepressant drugs. Chronic fluoxetine administration increases long-term potentiation (LTP) in the DG elicited in the absence of GABAAreceptor (GABAAR) inhibitors, and this effect depends on the newborn neurons [12].
In the presence of GABAAR inhibitors, DG LTP is reduced, perhaps due to occlusion, and long-term depression (LTD) is enhanced [12,57,58]. Enrichment and fluoxetine enable LTP in the adult rat visual cortex [48,59], and a similar effect of fluoxetine treatment on LTP was observed in the murine amygdala [60].
These findings may be related to the “dematuration” process observed after chronic fluoxetine administration in the dentate granule neurons [58], indicating that antidepressant treatment reactivated a juvenile-like plasticity in brain [48,60]. Enriched environment and perhaps also fluoxetine treatment during early life accelerate cortical maturation [61–63].
Conversely, chronic mild stress facilitates LTD in the CA1 area and chronic antidepressant treatment blocked this LTD facilitation and enhanced LTP [64]. Thus, chronic antidepressant treatment and enriched environment may increase synaptic plasticity in several brain areas (Figure 1), which may be consistent with the increased dendritic spine dynamics and turnover induced by antidepressant treatment [40]."
Try not to get lost in unappreciable effects of drugs. I see people tunnel vision on this sort of stuff all the time and it just never does them any good.
