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Skeletor

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Posts posted by Skeletor

  1. Why does Mirtazapine cause Restless Legs Syndrome? Mirtazapine is known to often provoke restless legs syndrome (RLS). Mirtazapine has an approximate 30% chance of inducing it; by comparison, paroxetine, sertraline, and other psychiatric medications only have an approximate 5% chance of causing RLS symptoms.

    Why is Mirtazapine prone to causing RLS?

    It's very interesting, especially that high percentage. No one seems to know why. They say that it might be due to its strong antihistamine properties. Some experts have proposed that it is due to its 5HT2 antagonist properties. But then other strong antihistamines and 5HT2 antagonists should also be prone to cause RLS, e.g. Amitriptyline, Nortriptyline, Doxepine etc., but they don't seem to cause it as frequently as Mirtazapine. One could argue that it is due to anticholinergic properties, which might have a counterbalancing effect.

    Some say that it may be Mirtazapine's pro-noradrenergic properties, but shouldn't we see it with other NRIs and pro-noradrenergic drugs? Many questions, no definitive answers...

  2. 10 hours ago, mikl_pls said:

    There are tertiary amine TCAs and secondary amine TCAs.

    The tertiary amines are all more serotonergic than noradrenergic, produce a secondary amine TCA as an active metabolite, and are generally more sedating than stimulating (until perhaps the levels of their active metabolites become significantly high enough).

    Amitriptyline as a tertiary amine is, when counting in its metabolite Nortriptyline, more noradrenergic than serotonergic... all in all.

  3. On 6/8/2020 at 10:17 PM, browri said:

    Yes this is the unfortunate part of Abilify along with Rexulti and Vraylar. Their long half-lives largely inhibit their use. However, I have been keeping an eye on patents. They are working on a Rexulti orally-disintegrating tablet. The patent request has already been submitted. It is feasible considering Rexulti's time-to-peak is only 4 hours with oral administration. I imagine with sublingual administration, it may be a useful emergent therapy in larger doses. We'll see how that evolves. And with Vraylar, I think the fact that they generally go right to 3mg after just a few days with normal dosing is overpowering the half life limitation to try and reach treatment efficacy. 

    Aren't long half lives good when it comes to psychotropics? Better than those SNRIs (Venlafaxine, Duloxetine) with their ridiculously short half lives and interdose-withdrawal... !?

  4. 10 hours ago, notloki said:

    It's an antidepressant up to 15 mg, above that it starts showing itself as an antipsychotic. I find it to be a strong antidepressant which compliments Wellbutrin and does not interfere with amphetamine treatment.

    It is one of the very few atypical antipsychotics that I would be willing to try... as adjunct for depression / for mood stabilization. Quite interesting drug.

  5. 19 hours ago, crazyguy82 said:

    I’ve had olanzapine didn’t do anything. Mirtazapine is great but I want to eat everything in sight! I’m really on the end of the line with meds.

    I hope it will improve over time. I have to say imipramine has significantly less side effects of any SSRI/SNRIS I’ve tired. Fingers crossed it will get better in time!

    Okay, then "Abilify" might be interesting.... partial agonist at D-Receptor(s), partial 5HT2C agonist, weak sedation @H1... Partial agonist at 5HT1A...

  6. Quote

    Since the introduction of the SSRIs, it has been repeatedly observed that severely depressed inpatients, usually those with melancholia, show a more robust response to TCAs than to SSRIs. The first studies to demonstrate this were by the Danish University Antidepressant Group, which published 2 widely cited studies showing the superiority of the TCA clomipramine to 2 SSRIs, citalopram and paroxetine, in hospitalized patients who had depression.19,20 Subsequent studies replicated the finding that TCAs are superior to SSRIs in specific populations.... 21-23 - source: https://www.psychiatrictimes.com/articles/not-obsolete-continuing-roles-tcas-and-maois

    It would seem so, at least according to many studies... Gillman regularly mentions that his patients did substantially better on TCAs than on SSRIs (Sertraline might be an exception). Especially Amitriptyline, Clomipramine and Imipramine seem to be superior in effectivity. Is it wise to completely shun those very effective older antidepressants?

  7. 1 hour ago, crazyguy82 said:

    I seem to be doing better. I feel awful stupid. I’m finding speaking difficult sometimes it almost feels I have to force my words out. I’m hoping this will go away. It is concerning as I have to speak all day for my job!

    I don’t normally feel medicated but I think I do now. I really don’t want to drop the imipramine.

    Something like Olanzapine (or Aripiprazole) might be better suited than "Seroquel"... Olanzapine has some potent 5T2 antagonism that should ease the side effects of Imipramine... Seroquel is primarily a strong antihistamine with some moderate NRI action, but you've already get enough NRI action with Imipramine.

    Alternatively Cyproheptadine if you can get it. Mirtazapine would also be a good choice.

  8. https://en.wikipedia.org/wiki/Amitriptyline

    https://en.wikipedia.org/wiki/Nortriptyline

    Both are quite similar, and that is no surprise, given that Notrtiptyline is Amitriptyline's major metabolite.

    When comparing both, we can ascertain the following: Amitriptyline has somewhat more SERT blocking going on, so might be slightly more "serotonergic" than Nortriptyline, although I am not quite sure if clinically relevant. Both are equally strong NRIs and 5HT2 antagonists. Amitriptyline is a stronger ALPHA1 blocker compared to Nortriptyline, so might cause more postural hypotension. Amitrptyline is a stronger antihistamine than Nortriptyline, so might cause more sedation and appetite. Amitriptyline is a stronger anticholinergic than Nortriptyline, so will probably cause more side effects. (Although stronger sedative and anticholinergic properties might be welcome, depending on the condition)

    What I am interested in: Who's been on both and how did they compare? (not only theoretically, but practically)

    binding affinities:

    nortgpk1f.png

    picture source: https://abload.de/img/nortgpk1f.png

     

  9. https://www.cambridge.org/core/journals/the-british-journal-of-psychiatry/article/clomipramine-tryptophan-and-lithium-in-combination-for-resistant-endogenous-depression-seven-case-studies/F3A1B19433959744DCF32C36C7B4A28F#

    Unquestionably an extreme combination, but it seems to exhibit powerful antidepressant effects. Clomipramine on its own is regarded by many as maybe the most powerful non-MAOI antidepressant, at least in clinical practice and inpatient care, although the side effects can be quite rough, but combined with Tryptophan and Lithium it seems to be further boosted in its effect size and response rate.

    Maybe worth trying before hopping on ECT / MAOIs...

    One has to be careful because it is a small sample case "study", but nonetheless quite interesting to read. I encourage all those who have a view or experience to share it with us, regarding the aforementioned medications and especially the combination. Greetings!

  10. On 5/29/2020 at 11:49 PM, MisterMelancholy said:

    Has anyone else felt the apathy/laziness symptoms on an SSRI, but have them eventually go way on their own? 

    In my experience? No....

    On 5/31/2020 at 12:33 AM, echolocation said:

    i had increased anhedonia when i started on clomipramine, and not too long after a dose increase i found it eased up quite a lot. clomipramine is a TCA, not an SSRI, but i figured i'd drop my two cents in.

    Clomipramine is probably the strongest SNRI on the market. Its NRI effect might ease the anhedonia to some degree...

  11. On 5/16/2020 at 3:55 PM, browri said:

    Indeed. Nortriptyline is a metabolite of amitriptyline. The parent drug is preferential to the serotonin transporter (SERT) over the norepinephrine transporter (NET) or the dopamine transporter (DAT), whereas the child prefers the opposite. This is why nortriptyline is often used as an augmenting agent. Additionally, while nortriptyline has clinically negligible effects on DAT, its potent inhibition of NET in the pre-frontal cortex would indirectly ramp up dopamine signaling as well, making nortriptyline a makeshift NDRI.

    Importantly though are nortriptyline's 5HT2A and 5HT2C antagonist properties, both of which can lead to additional norepinephrine and dopamine release. Compound this with NET inhibition and you've again got a really robust effect.

    Nortriptyline seems to have some evidence in smoking cessation as well. Again though, like other tricyclics, it has fairly strong anticholinergic effects:

    image.thumb.png.ec58d50e89c09b55781784ea16650b6b.png

     

    Because nortriptyline is more of an NRI, you can mix it with some MAOIs if it's done carefully, but it should be a last resort. More than likely the most robust combo would be with either selegiline or tranylcypromine as they are preferential for inhibition of MAO-B, which is responsible for the breakdown of norepinephrine and dopamine predominantly, as opposed to MAO-A, which prefers serotonin oxidation. The concern of course with combining an MAOI and any kind of serotonin reuptake inhibitor is serotonin syndrome. Nortriptyline's affinity for the SERT is lower, but still considerable. If you start both medications on their lowest doses and increase either medication in tiny increments, only changing one med at a time and also giving plenty of time between dose changes, but it can be done.

    They've even done Tranylcypromine + Amitriptyline ^^

    https://www.ncbi.nlm.nih.gov/pubmed/30106881

     

    7 minutes ago, crazyguy82 said:

    I have found reading this thread quite fascinating.

    I recently had to come off Moclobermide as it was out of stock. I don’t really get on with SSRI/SNRIs. Mirtazapine made me fat. I’ve just started imipramine only 25mg and I’m finding it challenging. My doctor did mention Nardil but I think they are reluctant and so am I. I take Seroquel, lamictal and gabapentin. The gaba is for nerve pain. The imipramine has taken that away completely. I have Ativan and Zopiclone PRN.

    I have treatment resistant depression and various anxiety disorders. Also get extremely rapid mood drops that last 60 seconds or so.

    Any suggestion would be appreciated.

    How so?

  12. On 4/3/2020 at 2:57 AM, mikl_pls said:

    I wasn't able to find much, but I too believe I suffer from this. I believe my antipsychotic also contributes to this as well.

    As for the antidepressant (specifically SSRI) induced indifference, I found one single link from pubmed that seemed to be somewhat reputable. I recommend checking it out. I'll summarize a little of it below.

     

    Personally I have gotten rid of it by adding a moderately high dose of desipramine (100 mg) to my SSRI. That's a secondary amine TCA which works primarily on norepinephrine (actually is the most selective NRI on the market in the US). Atomoxetine (Strattera) would work too theoretically (I've tried it and it didn't work too terribly great for me). Fluoxetine and atomoxetine was a good combination until Strattera went generic (then all hell broke loose).

    MAOIs are really great for depression that are treatment resistant (if you're able to find a psychiatrist who's willing to prescribe them). They're even more effective when prescribed with a stimulant, which is classically contraindicated, but can be done under the close supervision of an expert psychiatrist.

    Nortriptyline seems to be a popular addon.

    SSRI + Nortriptyline

    MAOI + Nortriptyline

  13. Apropos that stimulation / tickling. It felt more like some form of odd genital stimulation. I didn't have typical sexual arousal or sexy thoughts when it happened. It was really an unpleasant intrusive feeling that I had to get rid of via triple masturbation.

    It didn't feel like hypersexuality or normal (heightened) form of libido. It was like a tingling... it doesn't hurt you, but it is no pleasant feeling.

    Strange thing is that it also happened on higher dose of Promethazine (30mg), not only Mirtazapine.

  14. On 15mg of Mirtazapine I had RLS and some strange tickling feeling in my lower stomach. (I masturbated a lot to get rid of it.)

    On 15mg of Promethazine I am fine, but anything higher than 25mg and I get RLS and that tickling feeling.

    What is going on? Which mechanism is involved?

    https://academic.oup.com/sleep/article/43/2/zsz223/5610750

    "It simply seems like histamine might have a role in RLS. Could it be as simple as that blocking histamine H1 receptors is bad for RLS? Or is it due to some kind of indirect interaction histamine has with dopamine?"

    It would seem that this antihistamine theory might be true at least to some degree, although there are so many theories on RLS that it is difficult to see through it. Especially when you have antihistamine properties and anti-Dopamine properties rolled into one drug.

    But Mirtazapine doesn't seem to have anti-Dopamine properties, so leaves the antihistamine action as culprit of RLS....

    Promethazine has some anti D2 action, but it is ridiculously weak: D2=250,   5HT2A=170,   H1=1 [nM] from Gillman's website. I doubt that it will do much in that regard.

  15. On 4/16/2020 at 2:15 AM, Iceberg said:

    While the med is labeled for OCD, I’m not sure we can accurately generalize the effective dose ceiling for anyone who doesn’t have ocd. 

    Supposedly it inhibits 80% of SERT transporter at 10mg... that is one hell of a potent drug. So with 75mg you probably would have 95% SERT inhibition.

    https://en.wikipedia.org/wiki/Clomipramine#Pharmacodynamics

    There is also the notion that many TCAs might be "overdosed" in general...

    18 hours ago, bk93062 said:

    My understanding on Lamictal was that it was more or less side-effect neutral which is why I agreed to start it on top of the Anafranil. 

    Yes, that is a good combo. Makes sense to add Lamictal.

  16. On 4/10/2020 at 3:07 PM, browri said:

    Certainly. When you lower dopamine signaling and throw it out of balance with acetylcholine, it can cause restlessness. So the anti-cholinergic effects of of tricyclics on the one hand can caused blurred vision, urinary retention, cognitive issues, possibly contribute to combination by slowing down the GI, on the other hands it calms you down from a psycho-motor perspective.

    So acetylcholine antagonizes Dopamine? (in some form)

  17. I welcome you to rate all the psychotropic drugs which you took in the past or are taking in the present. A short explanation of your experience with the drug(s) would be helpful, so that we better understand your rating.

    Oh, and please tell us which conditions you treat(ed). Thanks.

    Rating Scale is from 0 to 5... "zero" being the worst, "five" being the best.

    _______________________________________________________________________________

    Sertraline 2 / 5 - subtle effects. Did help with psychosomatic ailments, derealization and cognition, but caused SSRI-typical apathy & indifference. Not sure if it did anything for my social anxiety and psychomotor agitation. At most minor effects. I did take it for two years.

    Mirtazapine 2 / 5 - elephant tranquilizer. Didn't like the severe sedation. Didn't sleep well on it, bad dreams. Caused RLS. Was good for appetite, weight gain and IBS. I was on it for two weeks.

    Promethazine Syrup / Drops 20mg / ml | 3 / 5 - I rather liked that one. At a lowish dose (15 drops or so) it has a nice calming effect on me, without sedating me too much. Lowers anxiety and agitated states. Brings order into chaos. Good for appetite and stomach. I take it occasionally.

    N-acetylcysteine (NAC) 2.5 / 5 - Is a good supplement. Heightened focus, less derealization, world seems more colorful. Interesting stuff. Definitely worth a try.

    ..............................

    Conditions treated: Anxiety, depressive states, psychomotor agitation, somatization disorder.

  18. 19 hours ago, browri said:

    @Skeletor So the first part is how increasing serotonin signaling causes a downstream increase in dopamine signaling and then the brain becomes desensitized over time and the patient enters anhedonia.

    Antidepressant-naive individuals often report starting antidepressants like SSRIs and feeling initial activation, agitation, anxiety, insomnia, irritability. "Things get worse before they get better." This is because serotonin reuptake inhibitors start working almost immediately even though we don't feel better for a few weeks. Upon initially inhibiting the serotonin transporter, serotonin will begin collecting in the synapses between neurons. This will increase activation, particularly, of 5HT1A receptors, which is how serotonin reuptake inhibitors are believed to ultimately mediate their effect (central 5HT1 activation, which causes downstream dopamine release).

    The brain responds fairly quickly by reducing serotonin output into the synapse, to reduce the rate at which serotonin collects there. Despite this compensatory mechanism to offset the impact an SRI has on the synapse, activation of 5HT1 receptors continues both pre- and post-synaptically. After a few weeks, the brain becomes desensitized to the activity at pre-synaptic receptors and these neurons begin releasing serotonin again. When this happens, this is when an antidepressant is believed to start working.

    The second part to this is the downstream release of dopamine that occurs upon 5HT1 activation. Dopamine receptors will respond to this in the same way. With increasing amounts of dopamine in the synapse, the brain will compensate by reducing dopamine output, DESPITE the 5HT1 activation. The net result after several weeks of administration of a serotonin reuptake inhibitor is much, much higher serotonin signaling along with a spike in dopamine signaling that then bottoms out and results, ultimately, in a net DECREASE in dopamine signaling. This is the chemical state of the brain in anhedonia.

    Doctors fight part 2 of the above process by swapping out the SSRI for an SNRI or by adding bupropion. Switching to the SNRI will inhibit norepinephrine reuptake, which will also further increase dopamine because the brain inter-converts these two neurotransmitters between each other and also because in the PFC, dopamine is largely transported between neurons by the norepinephrine transporter (NET) because this region of the brain possesses very limited quantities of the dopamine transporter (DAT).

    If you instead add bupropion to the SSRI, you do the same thing as switching to an SNRI with the added effect of DIRECT dopamine reuptake inhibition. Doctors will also take advantage of compounds that are antagonists of alpha-2 adrenergic receptors because these are auto-receptors that slow down the release of norepinephrine and serotonin. By blocking those receptors, serotonin and adrenergic activation is increased. A good example of this combo strategy is mirtazapine (Remeron).

    What's your take on tricyclics?

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