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This is what I have so far:

When you take an SSRI, it occupies the serotonin transporter, causing serotonin to remain in the synapse for longer. This activates postsynaptic serotonin receptors, some of which are beneficial to mood (e.g. 5-HT1A), some not so good (5-HT2C).

The good and bad 5-HT receptors are pretty evenly spread, so SSRIs produce both negative side-effects (sexual dysfunction, anhedonia, nausea, etc.) through activating the "bad" receptors, and positive antidepressant effects by triggering good receptors like 5-HT1A. Neither really dominate, which explains the neutrality felt by many users.

By blocking the unwanted receptors, we can activate the desired receptors without negative side-effects. This can be achieved with drugs like mirtazapine, which itself blocks 5-HT2A, 5-HT2C, 5-HT3, and some other less relevant ones. It would seem that by blocking negative receptors, we'd turn SSRIs into some sort of miracle-drug; devoid of side-effects.

Combining mirtazapine with sertraline myself (only for 2 days), however, I have observed that the "bad" receptors I talked about are only half the story. Mirtazapine does indeed block side-effects such as nausea and sexual dysfunction, but I still experienced an overall reduction in serotonin activation during my 2-day trial*. I conclude the following;

Negative effects of SSRIs are the result of two mechanisms: activation of nasty receptors listed above, plus activation of presynaptic (or otherwise) autoreceptors. Blocking the first mechanism eradicates side-effects only after several weeks (time taken for autoreceptors to adjust). During the first few weeks, you'll still get some bad feelings as those autoreceptors dampen serotonin output.

This leads me to my first question: how do SSRIs cause activation of autoreceptors? If they only increase intrasynaptic serotonin levels, how does this influence presynaptic receptors? Are some autoreceptors postsynaptic?

You can block one type of autoreceptor with a drug called pindolol, but I read that a few case reports showed an increase in aggression. I put this down to an increased activation of bad serotonin receptors; the first mechanism of side-effects seen in SSRIs. This would suggest that a combination of pindolol + mirtazapine could be an effective antidepressant in its own right, and even more so with an SSRI. I personally think such a combo could achieve the dizzy heights of MDMA intoxication, if augmented with a dopaminergic.

Second question; surely if SSRIs can downregulate autoreceptors in a couple of weeks, wouldn't pindolol do the opposite? Maybe we'll just have to live with the lag period. Perhaps if autoreceptor activation during SSRI treatment was reduced just to normal levels (i.e. enough to block the extra SSRI activation, but no further), we'd be able to avoid this.

Carrying on in the same vein as this, I think amisulpride could be used to eliminate the crash from DRIs (methylphenidate, for example), and to boost effects from the drug. It'd do this by blocking the DRI from [indirectly] activating those autoreceptors, which normally leaves us in a state of minimal dopamine after the drug wears off. Dopamine-releasers are a different story, as they actively deplete DA stores in the presynaptic cell.

Thanks to anyone that can help.

* My test for high levels of "good" serotonin function is this: I listen to some psytrance/goa music. If it sounds amazing, it's more than likely my 5-HT1A receptors are working their magic.
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