My theory for overnight PSSD upon 2nd, or 3rd SSRI

[PSSD’s_Master]

Here is my theory for the phenomenon of people instantly getting PSSD upon taking a 2nd or third SSRI, when they had no problem (or mild) on their first SSRI. This is extremely common, especially severe cases.

This is mainly caused by memory reconsolidation, which is caused by a prediction error. Your brain remembers SSRI#1, as a firing pattern between a specific set of neurons. Although SSRI#2 activates a similar activity pattern, and population of neurons, it is still vastly different.

After previously using SSRI#1, you introduce SSRI#2 which is similar enough to recall the memory of SSRI#1, but different enough to cause a memory prediction error. This causes this memory to become destabilized, and subject to reconsolidation. Reconsolidation can strengthen, weaken, or no change, to a memory depending on many factors.

SSRI’s are extremely potent inducers of synaptic plasticity. While this memory is fragile, the SSRI activates many pro LTP/memory signalling cascades. This memory is replaced, and is now significantly stronger.

If SSRI#2 was taken originally, without previous use of SSRI#1, there would be no memory reconsolidation amplification. SSRI#1 basically acts as a stepping stone for this.

I believe this aberrant drug memory is mainly what is keeping the epigenetic & structural changes stable. The epigenetic, and structural changes are what is keeping homeostasis impaired.

This theory is based off my knowledge of drug tolerance, drug induced plasticity, and various conditions with overlapping similarities to PSSD.

[Determined-Mind]

Interesting stuff. This same theory of memory and prediction could explain the persistent disorders induced by chronic stress (repeated trauma).

If you have any treatment ideas to regenerate the expression of the original genome...

[RazeEzaR]

Interesting stuff. This same theory of memory and prediction could explain the persistent disorders induced by chronic stress (repeated trauma).

If you have any treatment ideas to regenerate the expression of the original genome...

There is only one way. I figured it out. The reintroduction of the very original PSSD drug. I was close to curing myself but I ran out. I tried a lot of versions of the modern day Paxil but manufacturing has been changed by everybody.

[Determined-Mind]

This strategy has been tried before, and while some people have experienced some relief, I don't recall reading any stories of recovery.

Personally, I don't think it's the answer, because given the diversity of symptoms involved in some cases of PSSD (sexual, cognitive, emotional, energetic), it suggests changes in many systems (dopamine, glutamate, noradrenaline, melanocortin, opioids, etc.) and neurological structures (nuclei accumbens, hypothalamus, insula, amygdala, hippocampus...).

The serotonin system is not the only one to have undergone changes.

In short, for therapies to be effective, the complexity of symptoms and the neurological systems underlying them will undoubtedly have to be taken into account.

A short personal story: my physical anhedonia was aggravated by flibanserin, without me even having previously felt any relief from this symptom when taking the drug. A few months later, I reintroduced flibanserin and saw no improvement. Yet this seems to be the drug most likely to have aggravated this particular symptom.

(And I recently read in a Meso article published in Sexual Medicine Reviews that flibanserin can indeed worsen symptoms - which reinforces the hypothesis I had formulated to myself).

[Jaxx]

This strategy has been tried before, and while some people have experienced some relief, I don't recall reading any stories of recovery.

Actually there have been cases. I recall Ghost mentioning a friend that reinstated a quite high dosage of Zoloft and got cured over time. Also, low-dose ssri has several success stories.
However, there have been quite some cases where things got worse, so it is definately a risky strategy.

[PSSD’s_Master]

This strategy has been tried before, and while some people have experienced some relief, I don't recall reading any stories of recovery.

Actually there have been cases. I recall Ghost mentioning a friend that reinstated a quite high dosage of Zoloft and got cured over time. Also, low-dose ssri has several success stories.
However, there have been quite some cases where things got worse, so it is definately a risky strategy.

Yeah this all makes sense. Discrepancies in doses cause a memory prediction error, which temporarily destabilizes the previous SSRI/PSSD memory/engram and it’s a very potent synaptic plasticity inducer. This could drastically go either way depending on the circumstances/input. This is why I also hypothesized fluctuations in doses/dosing is a very significant risk factor for developing PSSD.

[RazeEzaR]

This strategy has been tried before, and while some people have experienced some relief, I don't recall reading any stories of recovery.

Actually there have been cases. I recall Ghost mentioning a friend that reinstated a quite high dosage of Zoloft and got cured over time. Also, low-dose ssri has several success stories.
However, there have been quite some cases where things got worse, so it is definately a risky strategy.

Yeah this all makes sense. Discrepancies in doses cause a memory prediction error, which temporarily destabilizes the previous SSRI/PSSD memory/engram and it’s a very potent synaptic plasticity inducer. This could drastically go either way depending on the circumstances/input. This is why I also hypothesized fluctuations in doses/dosing is a very significant risk factor for developing PSSD.

Hey I tried PMing you. Your theory is 100% what’s going on with me.

[Quinnmanne]

I don't fit into "overnight" group as my PSSD set in gradually as I slowly tapered. Only 1 SSRI used though but a few attempts to quit before. Also I've come across many stories with PSSD happening from one and only type of SSRI but only after 2nd or 3rd cycle on it. Therefore I doubt that the type of SSRI has not much to do with developing this. Fluctuation in dosage plays a role for sure.

[Wantmyclitorisback]

I have noticed a change in response to SSRIs over time, which is strange. The drug that gave me PSSD - Sertraline- I had briefly taken before as a teenager but did not experience genital numbness the first time, yet severe genital numbness the second time. Similarly, Citalopram gave me hypomania the first time I took it, nothing the second time I took it, and severe emotional numbness the third time I took it. All of this effects disappeared on discontinuation. Could this not just be that the brain is in a different state on introduction of the pills, though? I'm not sure I "buy" that it remembers the previous SSRI as I've been on a lot of these drugs and my experience of each one has been wildly different.