Only reason for switching, is that Donepezil made my RBD significantly worse due to having a very long half-life (70 hours), so I'm getting a cholinergic effect during my sleep time. Rivastigmine has a short one (1.5 hours), which should be more practical and manageable.
Symptoms before Donepezil trial:
--------------------------------------------------------------------------------------------------------- Flattened affect ("Flattened" in a sense that my best friend died and I felt nothing.
The only emotion I can feel is anger and irritability. Other than that, I'm a total zombie inside).
- Anhedonia (No longer feeling any pleasure from music or doing hobbies).
- Anorgasmia & erectile dysfunction.
- Brainfog from hell, physical and mental fatigue, very poor memory, and inability to focus.
- My baseline heart rate shot up to ~120 BPM and stayed there. My blood pressure went up to 150/95 mmhg.
All blood tests and examinations were normal (Kidney, liver, heart, electrolytes, hormones panel, ultrasonography, EEG, ECG, etc, etc)
Progress:
- Day 18 on Donepezil (6-2-2019):
Since this may be the last day on Donepezil, I tried augmenting it with the same agents I will be using with Rivastigmine to see how I would react:
- Rasagiline = 0.25 mg. (More gives me impulse control issues)
- Ginkgo Biloba = 50 mg b.i.d.
- Aspartame = 1 litre of diet coke (Aspartic acid and phenylalanine metabolites. It's poor man's Sarcosine + Phenylalanine, because they are not available where I live).
I tried these drugs previously, without Donepezil, with little success. This time, however, I notice a potent synergistic effect.
- Brain fog (100% improvement): Completely cleared. My thinking is crystal-clear and my focus is sharp, akin to pre-SRI level.
- Derealization/dissociation (85%): I feel drastically less dissociated. I'm more 'involved' with the world around me. No longer in a dreamy/hazy reality. However, there seems to be a moderate perceptive anomaly, especially around fluorescent lights.
- Flattened affect (10%): Still can't feel any emotions; very blunted. However, I do feel a small "nudge" on this combo, very mild and not comparable to the first days on Donepezil monotherapy. This is, by far, the most stubborn symptom to treat.
- Anhedonia (75%): Significant improvement compared to Donepezil-alone and to augments-alone. However, this is activity-specific. I still don't enjoy music and socialization, most likely due to the flattened affect, however I do enjoy watching movies and playing games, working out, etc.
- Libido (30-40%): It's 'there' if I work hard to "getting in the mood". I don't feel "lusting" over beautiful women spontaneously, nor do I experience any sexual fantasies.
- Erectile dysfunction (85%): There is a significant improvement, and I get random non-pleasurable erections when I lie down and when I wake up from a nap. I can maintain it for a much longer time. Although, they are not as hard as they used to be before antidepressant intake. My penis also seem ... smaller? I don't know, maybe my memory is playing tricks on me.
- Anorgasmia (50%): I can have orgasms now, although it's still difficult and takes long. This is because of improvement in genital anesthesia on this combo. Sometimes the orgasms are "explosive", to the point of vocalization. Refractory period is still super long, but it's better and I don't feel so dull after orgasms (less POIS).
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- Day 22 on Donepezil (10-2-2019):
Rivastigmine has not arrived yet, so I'm still on Donepezil. I'm noticing more increasing in libido and the reemergence of sexual fantasy and lusting. Morning wood and random erections are happening more consistently. Other than that, I've added 4 mg Cyproheptadine just last night (to be taken at bed time).
Why Cyproheptadine? It's a potent anti-serotonergic that's used in management of serotonin syndrome (SS). 5HT2 receptors downregulate in response to both agonism and antagonism. 5HT2C receptors are upregulated by inflammatory cytokines (GABA-A inflammatory subunits maybe?), and continue to fire even in the presence of serotonin. High 5HT2C density inhibits dopamine release, so downregulating those receptors would allow some recovery of frontocortical dopaminergic pathway, improving blunted affect.
Also, 5HT2C receptors inhibit reinforcing effect of many reinforcing drugs (i.e. stimulants and caffeine), so maybe that's why we lost the ability to get high on things after PSSD.
Cyproheptadine also drastically reduces ACTH release and is used off-label for Cushing's. It does so by interfering with CRF function on the pituitary, maybe by blocking CRF receptors.
Downside is that Cyproheptadine has anti-dopaminergic and anti-muscarinic effects, but in my case this is a good thing since I'll allow more refreshing sleep on Donepezil and when I wake up its effects would be minimal (half-life: 12 hours). Anyway, I increased Donepezil dose to 5 mg and Rasagiline to 0.5 mg.
Hopefully, presynaptic 5HT1A receptors would upregulate as well, since it's an antagonist. Also:
But other studies say that it has a weak androgenic effect at high doses.Cyproheptadine treatment resulted in a marked lowering of plasma ACTH concentrations (221-320 pg/ml). This was associated with an increase in both plasma LH and testosterone concentrations.
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- Day 24 on AChEIs (12-2-2019):
Today is the first day on Rivastigmine. It's very interesting to note that cholinergics fixed my post-antidepressant hypertension and tachycardia, which is expected since they are parasympathomimitic. Perhaps PSSD's sympathetic overactivation is due to cholinergic impairment.
I'm quitting Ginkgo Biloba since it's making my anhedonia worse (which has always been my reaction to it, btw). Glycine downregulation is a bitch. I'm adding NAC to my regimen, to upregulate tyrosine hydroxylase and get a bigger dopaminergic effect out of phenylalanine.
So, regimen is:
- Rivastigmine = yet to decide on dose.
- Rasagiline = 0.25 mg.
- Cyproheptadine = 4 mg (@ bedtime).
Supplements:
- N-acetylcysteine (NAC) = 600 mg (Tyrosine hydroxylase upregulation).
- B-complex (Folic acid + B12).
- Aspartame (Diet coke) = 1/2 litre (Phenylalanine + aspartic acid).
Improvements so far:
- Flattened affect (20%): My emotions are recovering, thanks to Cypro. This is the second day I have (mild) emotions, and the effects are getting stronger unlike previous windows of relief where I get 1 day of relief and the following day they are gone or get weaker. Cypro may be the answer to PSSD blunted affect, only time would tell.
- Cognitive dysfunction (100% recovery): Still doing good.
- Derealization/dissociation (100% recovery): After adding Cypro, dissociation has completely gone. 5HT2 antagonism and downregulation were the last piece of the puzzle.
- Anhedonia (50%): Anhedonia recovery took a hit thanks to Ginkgo. But this should improve soon. NAC would help recovering from Ginkgo's glycine downregulation, as well as upregulating tyrosine hydroxylase, so let's hope it gets better.
- Libido (50%): It has improved a lot. I enjoy the sight of beautiful women, but it's nothing like my pre-antidepressant libido. I caught myself fantasizing one time, so there's a definite improvement to last update.
- Erectile dysfunction (85%): It's too mild now to impair having sex. In fact, some days I can manage to have throbbing erections. My partner confirms that my penis size seem different, but this may be a trick of the memory since last time I had full erections was more than a year ago. Morning and nocturnal erections are still occurring.
- Anorgasmia (100%): It's much easier having orgasms thanks to Cypro. It's not too hard and it's not too fast as to have premature ejaculation. POIS is minimized and refractory period is down to 2 days (!!).
Overall, I'm closing in on PSSD. Hopeful for complete recovery.
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- Day 34 on AChEIs (22-2-2019):
I needed to redose Rivastigmine every 2-3 hours, which proved to be too inconvenient. I went back on Donepezil a couple of days ago. It's superior anyway since it's a sigma-1 agonist. I'll think more on how to counteract RBD.
Cyproheptadine continues to make me groggy, but it's getting much more tolerable since I'm developing a tolerance to the antihistamine effects. I apologize for not replying to PMs, I can't focus still.
New status:
- Flattened affect (30%): It has gotten better since last update, ever so slightly. I'm starting to experience surges of emotions but they are short-lived. The good news is that there is no reduction in the 30% improvement.
- Anhedonia (50%): No improvement since last update, despite of quitting Ginkgo. It must be Cypro's dopamine antagonism. I'm going to raise Rasagiline's dose to 0.5 or 1 mg until I'm done with the Cypro course. I notice an appetite boost even after Cypro is out of my system, so 5HT2 receptors must have started to downregulate.
- Libido (85%): Massive improvement, but still not back to baseline. I'm starting to fantasize more frequently about sex and crave it daily. I enjoy the sight of sexy ladies even more, and legs can be addictive. My refractory period is down to 12 hours. On some of the days, I try to have 2 orgasms. I believe that Cypro's ACTH inhibition is the reason for this recent improvement, having a synergistic effect on libido and on hippocampal health. (Stress/cortisol causes hippocampal atrophy). That said, I used to be hypersexual before PSSD, thinking about sex most of the day and my refractory period was 1 hour or less.
- Erectile dysfunction (100%): I no longer experience any erectile dysfunction. However, there remains some residual loss of genital sensitivity.
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- Day 43 on AChEIs (3-3-2019):
I still retain the sexual and cognitive improvements, but anhedonia and blunted affect are getting worse.
New changes:
- Flattened affect (10%).
- Anhedonia (30%).
I cannot find a viable option to increase dopamine release on a budget. Tonic dopamine release (Rasagiline) isn't helping, which isn't surprising. For anhedonia and blunted affect, one needs phasic dopamine releaser (A stimulant like amphetamine or methylphenidate). Tonic dopaminergics are nearly useless for these conditions.
That said, I've decided to target the opioid receptors instead. Phasic dopamine release (and emotions, music, etc) induce a hedonistic response via downsteam glutamatergic and finally opioidergic activation. It all comes down to mu opioid activation, downsteam. Therefore, upregulating mu opioid receptors by low dose Naltrexone (LDN) should prove to be pro-hedonistic.
My regimen would be:
- Donepezil: 2.5 mg.
- Cyproheptadine: 4 mg.
- LDN: 5 mg.
- NAC: 600 mg
- Diet coke.
As for Rasagiline, I'm debating whether I'll keep taking it or not. I'll think more about it.
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- Day 73 on AChEIs (2-4-2019):
I have tried Baclofen + Memantine combo for 7 to 10 days and it restored my emotions, but it gave me incredible dizziness, nausea, and vomiting that not even Metoclopramide was able to suppress. I quit taking Baclofen, but continued to take Memantine.
I also learned that Baclofen indirectly induces serotonin release and activation of postsynaptic 5HT1A receptors. This would explain why it restored my emotions, since postsynaptic 5HT1A receptors are probably downregulated too much because of SSRI's induced changes to SERT mRNA expression causing bombardment of 5HT1A receptors and GIRK channel decoupling. Here's the study relative to Baclofen:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2943331/
I'm still very functional sexually. I have sex daily and sometimes once every 2 days, but it's not passionate since I experience no emotions or closeness. It's just mechanical, sorta like shooting a porn. However, without ginkgo biloba I experience a degree of erectile dysfunction, so I've been taking it frequently.
I give up on trying to fix blunted affect without amphetamine or other phasic dopamine releasers. That said, I think Saint John's Wort (SJW) would be an interesting drug since it upregulates postsynaptic 5HT1A receptors, so it could restore my emotions.
Postsynaptic 5HT1A receptor activation induces oxytocin release, endorphin release, as well as cortisol and prolactin release. Oxytocin and endorphin could explain Baclofen's pro-emotional effect via indirect postsynaptic 5HT1A activation.
I've decided that since I can't afford phasic releasers, I'd stick with Rasagiline and take Memantine to keep tolerance down.
Donepezil works better than Rivastigmine for me. I also noticed that when I avoid proteins, my sleep quality becomes significantly better, so I'm eating the minimal requirement of proteins.
Current regimen:
- Donepezil: 2.5 mg.
- Rasagiline: 0.25 mg.
- Memantine: 20 mg.
PRN (As-needed):
- Ginkgo biloba extract: 50 mg.
- NAC: 600 mg
- Diet coke.
- B12 + zinc + folic acid.
Status:
- Cognitive dysfunction (100% recovery).
- Derealization/dissociation (100% recovery).
- Anorgasmia (100% recovery).
- Libido (75% recovery): It could be better.
- Erectile dysfunction (75% recovery): Can maintain an erection easily, but could be better. Ginkgo is always needed.
- Anhedonia (50%): I enjoy doing my job, and I enjoy playing games and reading the news. My anhedonia is social in nature. I don't feel the inner "drive" to talk to people and I don't enjoy it when I force myself to interact. I also don't enjoy music that I used to love. This is all oxytocin and dopaminergic in nature. (Postsynaptic 5HT1A and phasic dopamine release). I can't fix this for the time being.
- Flattened affect (10%): The most stubborn symptom. Glutamate seems to play a major rule, but what's strange is that sometimes I feel a short-lived surge of emotions after taking Memantine. Maybe I have excess glutamatergic function regarding only certain receptors or brain areas. I remember that I lost my emotions before PSSD only during benzodiazepine withdrawal. I will think deeply about a 2-week dextromethorphan trial, I'll let you know my decision if I make one.
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- Day 83 on AChEIs (22-4-2019):
I'm in the process of finalizing my regimen to achieve near 100% symptomatic relief using minimal doses and the least amount of drugs needed. Since I've been noticing tolerance on Donepezil, I'm going to switch to Rivastigmine since it's pseudo-irreversible, and according to this study, doesn't cause enzymatic upregulation (tolerance).
I also have some very good news. Unlike Donepezil, Rivastigmine doesn't cause dizziness, nausea, and vomiting when combined with Baclofen, so I'll be adding Memantine and Baclofen again.
I have also figured out a way to tolerate Cyproheptadine's side effects. Last time I've titrated it up, I managed to get over all the side effects with the exception of the sharp increase in joint inflammation due to its ability to inhibit CRH release and lowering cortisol (I suffer from mild rheumatoid arthritis). I literally couldn't walk last time I was on Cypro for more than a week. However, I found a drug in my country's pharmacopoeia called Diacerein, which works by inhibiting IL-1 beta, IL-6, and TNF-alpha. It's been helping a lot with joint inflammation and I'm finally able to tolerate Cyproheptadine on it.
So, current regimen:
- Cyproheptadine: 2 mg b.i.d.
- Rivastigmine: 1.5 mg t.i.d.
- Rasagiline: 0.25 mg.
- Memantine: 20 mg.
- Baclofen: 25 mg.
PRN (as-needed):
- Diet coke.
- B-complex.
Status:
- Cognitive dysfunction (100% recovery).
- Derealization/dissociation (100% recovery).
- Anorgasmia (100% recovery).
- Erectile dysfunction (100% recovery).
- Anhedonia (100% recovery).
- Flattened affect (100% recovery): I feel human again, thanks to Baclofen + Cyproheptadine.
- Libido (80% recovery): Memantine usually floors my libido, but Cypro is preventing that from happening. This is the main reason I got back on Cypro. Memantine is essential to preventing tolerance to Baclofen. Without Memantine, libido would be 100%.
Overall, I'm happy with the result even if I'm needing low doses of 5 drugs. I feel pretty functional. Until one day I feel comfortable with reversing/curing my PSSD and potentially re-triggering my severe anxiety disorder. But I don't see that happening soon.
down.