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My question is strictly related to its sedating effect, how is it different from for example Mirtazapine or tricyclic antidepressants? Does Seroquel differ from the mentioned antidepressants in terms of how it causes sedation? How does it work exactly?

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a lot of it has to do with histamine action... all three meds have a strong effect (depending on the TCA) on histamine receptors which leads to sedation. Often the effect is dose dependent - seroquel often becomes less sedating at midrange doses (maybe 300-600mg) because it starts to effect the adrenergic system, but gets sedating again at 600+ because dopamine blockade gets stronger. Remeron has a similar deal, noradrenergic effects offset antihistamine and other sedation effects as the dose goes up. All three treat depression in different ways. Remeron is referred to is as Noradrenergic and Specific Serotoninergic antidepressant and doesn’t directly effect the reuptake of serotonin/norepinephrine like other antidepressants.

@browri is a good source for all the technical stuff 

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Posted (edited)
On 1/4/2021 at 5:17 AM, Isaiah2017 said:

My question is strictly related to its sedating effect, how is it different from for example Mirtazapine or tricyclic antidepressants? Does Seroquel differ from the mentioned antidepressants in terms of how it causes sedation? How does it work exactly?

 

On 1/4/2021 at 12:14 PM, Iceberg said:

a lot of it has to do with histamine action... all three meds have a strong effect (depending on the TCA) on histamine receptors which leads to sedation. Often the effect is dose dependent - seroquel often becomes less sedating at midrange doses (maybe 300-600mg) because it starts to effect the adrenergic system, but gets sedating again at 600+ because dopamine blockade gets stronger. Remeron has a similar deal, noradrenergic effects offset antihistamine and other sedation effects as the dose goes up. All three treat depression in different ways. Remeron is referred to is as Noradrenergic and Specific Serotoninergic antidepressant and doesn’t directly effect the reuptake of serotonin/norepinephrine like other antidepressants.

@browri is a good source for all the technical stuff 

I mean @Iceberg you actually covered it really nicely. It's also good that the OP is truly comparing three completely different fruits in this case (actually 3.5, but I'll get to that in a second), as you can stack effects on top of each other to further describe the next. For example, mirtazapine at the bottom of the dose range largely achieves its sedation via antagonism of the histamine type 1 receptors. Histamine controls alertness of various bodily processes. It intertwines beautifully with orexin to regulate the sleep-wake states. It controls the alertness of our immune system (itchiness/allergies). It controls acid production in the stomach (e.g. famotidine is an acid reducer that works by blocking histamine receptors in the stomach lining). So you take this kind of effect and step up to quetiapine, which at the bottom end of the dose range is also largely an antihistamine like mirtazapine, but it also adds alpha-1 adrenergic antagonism, which calms the cardiac system. A step further with tricyclic antidepressants and you introduce anticholinergic effects which are sedating in a wholly different way. Diphenhydramine (common household Benadryl) mediates a lot of its sedation through central histamine type 1 antagonism, but most people don't realize how potent of an anticholinergic it is as well, which contributes to this sedation. And just based off my own experience with benztropine (Cogentin), I can personally say I couldn't do basic arithmetic and my eyes were going out of focus.

Anywho........I said 3.5 earlier because quetiapine should be qualified as either immediate release or sustained release. There truly was no need to prolong quetiapine's presence in the bloodstream by creating an extended release tablet. What the manufacturer hoped to achieve was increased exposure to the metabolite, norquetiapine. This would have made Seroquel a stronger 5HT1A partial agonist, 5HT2 antagonist (broad-spectrum), 5HT7 antagonist (serotonin auto-receptor), while also having less adrenergic antagonism, more muscarinic acetylcholine antagonism, and more norepinephrine reuptake inhibition. This had the potential to increase Seroquel's efficacy in affective/mood disorders (XR) versus in bipolar disorder and or schizophrenia (IR), the initial target populations for Seroquel.

With increasing dosage of mirtazapine, you introduce considerable antagonism of 5HT2A/C, which would contribute to increased norepinephrine and dopamine output. What makes mirtazapine unique is that it also has considerable alpha-2 adrenergic antagonism (auto-receptors) without also blocking alpha-1. This has a net activating effect because blocking alpha-2 receptors will increase the release of serotonin and norepinephrine, but without also blocking alpha-1 receptors, it will feel stimulating like a norepinephrine reuptake inhibitor. This downstream effect that alpha-2 antagonism has on serotonin release also makes mirtazapine an indirect activator of central 5HT1 receptors without inhibiting serotonin reuptake, and this can be very effective for some patients.

With increasing dosage of quetiapine (i.e. the "depression range" = ~100-300mg), similarly to mirtazapine, it begins to activate the adrenergic system because quetiapine is a potent alpha-2 antagonist and its metabolite, norquetiapine, is a strong norepinephrine reuptake inhibitor. Whether you take the immediate or extended release, one of the compounds will increase adrenergic tone. At these doses, quetiapine begins to bind to and block serotonin auto-receptors, thus increasing serotonin release in a similar way to mirtazapine. This is in tandem with norquetiapine's direct partial agonism of 5HT1A receptors, which would assist greatly in depressive episodes without the instability risk of serotonin reuptake inhibition.

Tricyclics are much the same as the last two, but they add the TRIPLE whammy of also being serotonin-norepinephrine reuptake inhibitors, which has a net-enhancing effect across the board.

When you get to the top of quetiapine's dose range, it begins to saturate and block dopamine receptors in a way that makes it more antipsychotic than anything else. Mirtazapine, on the other hand, has little impact on dopamine signaling. It is a ligand for these receptors, but at very low affinity, which is ironic considering that as a metabolite of mianserin, mirtazapine is in fact a structural analogue of asenapine (Saphris). It is not uncommon for atypical antipsychotics like asenapine to cut the proverbial brake lines (such as blocking alpha-2 receptors to increase serotonin and norepinephrine signaling). What is unusual is for a compound to cut the brake lines and not dampen the chain reaction (like blocking alpha-1 and alpha-2 at the same time). Doing the latter would have the net effect of enhancing serotonin signaling but not norepinephrine, and serotonin activation of 5HT2 would reduce norepinephrine output. Good thing mirtazapine is blocking 5HT2 receptors.

Edited by browri

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9 hours ago, browri said:

 

I mean @Iceberg you actually covered it really nicely. It's also good that the OP is truly comparing three completely different fruits in this case (actually 3.5, but I'll get to that in a second), as you can stack effects on top of each other to further describe the next. For example, mirtazapine at the bottom of the dose range largely achieves its sedation via antagonism of the histamine type 1 receptors. Histamine controls alertness of various bodily processes. It intertwines beautifully with orexin to regulate the sleep-wake states. It controls the alertness of our immune system (itchiness/allergies). It controls acid production in the stomach (e.g. famotidine is an acid reducer that works by blocking histamine receptors in the stomach lining). So you take this kind of effect and step up to quetiapine, which at the bottom end of the dose range is also largely an antihistamine like mirtazapine, but it also adds alpha-1 adrenergic antagonism, which calms the cardiac system. A step further with tricyclic antidepressants and you introduce anticholinergic effects which are sedating in a wholly different way. Diphenhydramine (common household Benadryl) mediates a lot of its sedation through central histamine type 1 antagonism, but most people don't realize how potent of an anticholinergic it is as well, which contributes to this sedation. And just based off my own experience with benztropine (Cogentin), I can personally say I couldn't do basic arithmetic and my eyes were going out of focus.

Anywho........I said 3.5 earlier because quetiapine should be qualified as either immediate release or sustained release. There truly was no need to prolong quetiapine's presence in the bloodstream by creating an extended release tablet. What the manufacturer hoped to achieve was increased exposure to the metabolite, norquetiapine. This would have made Seroquel a stronger 5HT1A partial agonist, 5HT2 antagonist (broad-spectrum), 5HT7 antagonist (serotonin auto-receptor), while also having less adrenergic antagonism, more muscarinic acetylcholine antagonism, and more norepinephrine reuptake inhibition. This had the potential to increase Seroquel's efficacy in affective/mood disorders (XR) versus in bipolar disorder and or schizophrenia (IR), the initial target populations for Seroquel.

With increasing dosage of mirtazapine, you introduce considerable antagonism of 5HT2A/C, which would contribute to increased norepinephrine and dopamine output. What makes mirtazapine unique is that it also has considerable alpha-2 adrenergic antagonism (auto-receptors) without also blocking alpha-1. This has a net activating effect because blocking alpha-2 receptors will increase the release of serotonin and norepinephrine, but without also blocking alpha-1 receptors, it will feel stimulating like a norepinephrine reuptake inhibitor. This downstream effect that alpha-2 antagonism has on serotonin release also makes mirtazapine an indirect activator of central 5HT1 receptors without inhibiting serotonin reuptake, and this can be very effective for some patients.

With increasing dosage of quetiapine (i.e. the "depression range" = ~100-300mg), similarly to mirtazapine, it begins to activate the adrenergic system because quetiapine is a potent alpha-2 antagonist and its metabolite, norquetiapine, is a strong norepinephrine reuptake inhibitor. Whether you take the immediate or extended release, one of the compounds will increase adrenergic tone. At these doses, quetiapine begins to bind to and block serotonin auto-receptors, thus increasing serotonin release in a similar way to mirtazapine. This is in tandem with norquetiapine's direct partial agonism of 5HT1A receptors, which would assist greatly in depressive episodes without the instability risk of serotonin reuptake inhibition.

Tricyclics are much the same as the last two, but they add the TRIPLE whammy of also being serotonin-norepinephrine reuptake inhibitors, which has a net-enhancing effect across the board.

When you get to the top of quetiapine's dose range, it begins to saturate and block dopamine receptors in a way that makes it more antipsychotic than anything else. Mirtazapine, on the other hand, has little impact on dopamine signaling. It is a ligand for these receptors, but at very low affinity, which is ironic considering that as a metabolite of mianserin, mirtazapine is in fact a structural analogue of asenapine (Saphris). It is not uncommon for atypical antipsychotics like asenapine to cut the proverbial brake lines (such as blocking alpha-2 receptors to increase serotonin and norepinephrine signaling). What is unusual is for a compound to cut the brake lines and not dampen the chain reaction (like blocking alpha-1 and alpha-2 at the same time). Doing the latter would have the net effect of enhancing serotonin signaling but not norepinephrine, and serotonin activation of 5HT2 would reduce norepinephrine output. Good thing mirtazapine is blocking 5HT2 receptors.

O´ wow, that´s a tremendous amount of information to digest in one go! Thanks man! Much appreciated!

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2 hours ago, Isaiah2017 said:

O´ wow, that´s a tremendous amount of information to digest in one go! Thanks man! Much appreciated!

No problem. Looking back on that post from last night I was a bit hypomanic and it was a tad of a brain dump, but a more succinct answer to your question is that all three (mirtazapine, quetiapine, tricyclics [e.g. doxepin or amitriptyline]) are very potent antagonists of histamine in the brain in small doses. In the central nervous system, that's responsible for wake/sleep. All three are strongly pro-adrenergic with increasing doses making them all stimulating in the mid-range, but at the top of the range, quetiapine could stand to become sedating again like the bottom end of its dose range due to significant D2 antagonism, which @Iceberg so kindly pointed out. Being devoid of significant dopamine antagonism themselves, mirtazapine and tricyclics will just allow their pro-dopaminergic effects to stimulate those receptors instead of blunting that response as an antipsychotic would. Herein lies the antidepressant effect. Mirtazapine in particular succeeds by cutting brake lines (i.e. antagonizing receptors that would slow the release of other neurotransmitters. E.g. alpha-2C antagonism increases serotonin and norepinephrine, 5HT2A/C antagonism increases norepinephrine and dopamine output in the pre-frontal cortex, which at higher doses should put it on the stimulating portion of the antidepressant spectrum along with bupropion.

With all the time I spent writing that last post and this one, I think I've convinced myself to ask my doctor if I can try mirtazapine in place of Trintellix+Rexulti. :P 

 

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