Receptor downregulation & SSRI. Linear relationship with dosage?

[Paydude]

My understanding of SSRI mode of effect is this:

1. They inhibit reuptake of serotonin, making it abundant in the brain
2. Your receptors first compensate by dropping serotonin levels (which is why anxiety/depression gets worse in first few days of administration)
3. At some point, your receptors "give in" to this serotonin abundance and stop trying to regulate it. Serotonin levels get back up.
4. In reaction, the number of the receptors themselves are downregulated. This is aparently where the bulk of mood improvement is observed (which sounds counter intuitive to me).

My question is this: Is the eventual amount of receptor downregulation dosage dependent, ie, is there a linear relationship, or is there a dosage before which there is hardly any downregualtion, past which, say, 90% of your receptors downregulate?

I ask because I'm dosing up (just relapsed) and trying to hit that sweet spot where my anxiety is no longer catastrophic, and yet I can still feel enough anxiety so that the bulk of my improvement comes from desensitization during exposure therapy. I seem to have done this 7 years ago on 50 mg/day Luvox and the result was exactly that. My panic during exposure was manageable, but still present enough that I developed real coping skills. I believe this is why I was panic free for 7 years on 50 mg /day Luvox alone. And I felt real emotions too.

I dropped the dose 3 months ago and relapsed, and now the 50 mg/day doesn't seem to work anymore. I want to raise the dose and find that exact point again. Will it be possible for me to find a higher dosage that will be as calming as my original dose and still allow some feeling, by experimenting, or will the receptor downregulation be exponential past a certain point and zombify me useless?

Thanks for attempting to answer this awkwardly presented question from a layman.

[insights]

My understanding of SSRI mode of effect is this:

1. They inhibit reuptake of serotonin, making it abundant in the brain

Yes, they inhibit reuptake in the synapses, so it hangs around in the synaptic cleft and it is therefore more likely that a serotonin molecule will bind with a serotonin receptor. They may also increase serotonin synthesis and expression in the short term.

2. Your receptors first compensate by dropping serotonin levels (which is why anxiety/depression gets worse in first few days of administration)

No. The increased anxiety is caused by the added serotonin. Despite what is often claimed, serotonin isn't the "feel good" neurotransmitter. Just the opposite, as serotonin reuptake inhibiting antidepressants demonstrate. OTOH, increased anxiety and depression are not common initial side-effects tianeptine (Sablon) a Selective Serotonin Reuptake Enhancer.

3. At some point, your receptors "give in" to this serotonin abundance and stop trying to regulate it. Serotonin levels get back up.

No, just the opposite. Serotonin synthesis and expression and overall levels drop dramatically in some brain regions and stay down, in other areas they drop and then rebound to baseline. See my: Serotonin: The 'chemical imbalance' myth

4. In reaction, the number of the receptors themselves are downregulated. This is aparently where the bulk of mood improvement is observed (which sounds counter intuitive to me).

But this isn't really why people improve, though it might be part of the trigger, or a consequence of what does, neurogenesis (Malberg JE, 2000; Perera TD, 2011). The current theory is that all the changes antidepressants make reverse atrophy of the hippocampi caused by stress hormones, mainly cortisol (Sapolsky RM, 2001).

My question is this: Is the eventual amount of receptor downregulation dosage dependent, ie, is there a linear relationship, or is there a dosage before which there is hardly any downregualtion, past which, say, 90% of your receptors downregulate?

If we replace "down regulation" with "neurogenesis," yes there is probably a relationship between dose and the degree of neurogenesis boosting, although I am unaware of any studies showing the effect is necessarily linear.  We know the effect is dose dependent because every antidepressant has a therapeutic dose range below which there is little positive effect.

My panic during exposure was manageable, but still present enough that I developed real coping skills. I believe this is why I was panic free for 7 years on 50 mg /day Luvox alone. And I felt real emotions too.

Maybe surprisingly, most people on antidepressants do continue to feel real emotions.

I dropped the dose 3 months ago and relapsed, and now the 50 mg/day doesn't seem to work anymore.

For reasons that aren't well understood, antidepressants tend not to work as well the second time around, often requiring a higher dose to achieve the previous response. They also often produce more severe initial side-effects which can also be different to when the drug was taken previously.

I want to raise the dose and find that exact point again. Will it be possible for me to find a higher dosage that will be as calming as my original dose and still allow some feeling, by experimenting, or will the receptor downregulation be exponential past a certain point and zombify me useless?

I don't know why it wouldn't be possible. If any antidepressant turns you into a zombie, then it isn't the right one for you. This isn't the norm, except maybe initially as the brain struggles to adapt, but this shouldn't last.

Ian

[Paydude]

I highly appreciate the comprehensive answers Ian. I'm at 75 mg/day now, and will hang in there for a few weeks. If my panic attacks don't go down from lasting 20 min to 10 seconds (like they used to be, which is where I want it) I'll move to 100 mg. If no results, I'll change to something else. Thanks.

[EclecticJoe]

Ian:

You keep saying for reasons that aren't well understood, antidepressants tend to have a different effect the second time around. Surely there is some valid theories out there why this happens isn't there?

[insights]

Surely there is some valid theories out there why this happens isn't there?

Lots of people have ideas, but it's anyone's guess if any are right. There is nothing in the medical literature so far and I'm not expecting there will be anytime soon. This is still fairly new. Psychiatrists have been aware of antidepressant poop-out (tachyphylaxis) for at least 3 decades and no definitive cause for it has yet been determined. Indeed, researchers are still arguing whether it is a real phenomenon, or if poop-out just shows that the drug never worked in the first place and the period of effectiveness was just the placebo effect. I assume that both phenomena are linked by similar biology.

Ian