Psycho-Babble Medication Thread 1116890

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Best serotonin 5-HT2C antagonist?

Posted by undopaminergic on September 10, 2021, at 12:07:42

What are the best serotonin 5-HT2C inhibitors clinically available?

I'm thinking such a drug could prevent Parkinson's-like adverse effects (especially apathy) of serotonin reuptake inhibitors. So I'm thinking of using it in combination with sertraline or clomipramine.

-undopaminergic

 

Re: Best serotonin 5-HT2C antagonist?

Posted by linkadge on September 10, 2021, at 16:54:14

In reply to Best serotonin 5-HT2C antagonist?, posted by undopaminergic on September 10, 2021, at 12:07:42

Clomipramine, to some degree is a 5-ht2c antagonist. Many of the TCAs are 5-ht2a/c antagonists.

There are no available selective 5-ht2c antagonists. The closest is agomelatine, but I don't think this is available in the US.

Others would include TCAs, mirtazapine, cyproheptadine and atypical antipsychotics.

I sometimes combine mirtazapine and cyproheptadine. I believe that mirtazapine is an inverse agonist which confers some additional properties over traditional antagonists.

A selective 5-ht2c antagonist would be quite useful (in my opinion).

Linkadge

 

Re: Best serotonin 5-HT2C antagonist?

Posted by undopaminergic on September 10, 2021, at 17:27:42

In reply to Re: Best serotonin 5-HT2C antagonist?, posted by linkadge on September 10, 2021, at 16:54:14

> Clomipramine, to some degree is a 5-ht2c antagonist. Many of the TCAs are 5-ht2a/c antagonists.
>
> There are no available selective 5-ht2c antagonists. The closest is agomelatine, but I don't think this is available in the US.
>

It is available here in Europe (EU). However, its half-life is only 1--2 hours, which does not sound useful:
https://en.wikipedia.org/wiki/Agomelatine

I used it many years ago, but did not notice an effect.

> Others would include TCAs, mirtazapine, cyproheptadine and atypical antipsychotics.
>

Yes. I'm thinking asenapine (Saphris, Sycrest):
https://en.wikipedia.org/wiki/Asenapine

Of all receptors, it has the greatest affinity for 5-HT2C.

> I sometimes combine mirtazapine and cyproheptadine. I believe that mirtazapine is an inverse agonist which confers some additional properties over traditional antagonists.
>

Asenapine is derived from mianserin like mirtazapine.

Last time I checked, sertindole was also an inverse agonist at 5-HT2C. I tried it, but had to cease it very soon due to extreme nasal congestion.

> A selective 5-ht2c antagonist would be quite useful (in my opinion).
>

Yes, absolutely.

There are some used in research, and I tried to acquire them years ago, but failed.

-undopaminergic

 

Re: Best serotonin 5-HT2C antagonist?

Posted by SLS on September 12, 2021, at 0:47:14

In reply to Re: Best serotonin 5-HT2C antagonist?, posted by linkadge on September 10, 2021, at 16:54:14

Hi.

Ritanserin is probably the most selective 5-HT2 antagonist in the world. When I looked in on it a bunch of years ago, it was reported to be virtually devoid of side effects. It is a drug without an indication. It has no other purpose that I recall other than being an antidepressant augmenter. By itself, it is inert.


- Scott

 

Re: Best serotonin 5-HT2C antagonist? SLS

Posted by undopaminergic on September 12, 2021, at 8:30:01

In reply to Re: Best serotonin 5-HT2C antagonist?, posted by SLS on September 12, 2021, at 0:47:14

> Hi.

Hi.

> Ritanserin is probably the most selective 5-HT2 antagonist in the world. When I looked in on it a bunch of years ago, it was reported to be virtually devoid of side effects. It is a drug without an indication. It has no other purpose that I recall other than being an antidepressant augmenter. By itself, it is inert.
>
>
> - Scott

But ritanserin is not clinically available as far as I know.

-undopaminergic

 

ritanserin, pimavanserin, and lumateperone undopaminergic

Posted by SLS on September 12, 2021, at 12:52:04

In reply to Re: Best serotonin 5-HT2C antagonist? SLS, posted by undopaminergic on September 12, 2021, at 8:30:01

Hi, UD.


> Hi.
>
> > Ritanserin is probably the most selective 5-HT2 antagonist in the world. When I looked in on it a bunch of years ago, it was reported to be virtually devoid of side effects. It is a drug without an indication. It has no other purpose that I recall other than being an antidepressant augmenter. By itself, it is inert.
> >
> >
> > - Scott


> But ritanserin is not clinically available as far as I know.
>
> -undopaminergic

Exactly.

Ritanserin is a great drug without an indication. What clinical value does this drug have as monotherapy? None. However it's possible that ritanserin would be a miracle augmenter of antidepressant treatment.

Ritanserin acts as a "selective" ligand of:

1. 5-HT2a receptors (Ki = 0.45 nM)
2. 5-HT2c receptors (Ki = 0.71 nM).

Ritanserin is labeled either a "selective" or "non-selective", depending on the authors of the available medical literature. At these receptors, ritanserin functions as an INVERSE AGONIST. An inverse agonist really acts as a super-antagonist. If a receptor is antagonized (blocked), it prevents the neuron from being stimulated in a neutral fashion. For example, let's say that the baseline level of neuron excitability in the absence of pharmacological intervention neuronal = 100 units. A pure antagonist might bring the excitability of the the neuron down = 0 units. Now, an "inverse agonist", when bound to the same receptor, will move the level of excitability to *below* the baseline = negative (-) 100. The inverse agonist actually suppresses the excitability of a neuron *below* its baseline. In a way, an inverse agonist actually causes a cell to do exactly the *opposite* of what an agonist does.

Although sometimes considered to be non-selective for all of the three subtypes of 5-HT2 receptors, Ritanserin really isn't. It does not bind to the 5-HT2b receptor subtype.

There are three drugs other drugs that are supposed to be potent 5-HTa/c antagonists:

1. Pimavanserin
2. Roluperidone
3. Lumateperone.

Unlike ritanserin, these drugs have other pharmacological properties. They aren't "clean". Of these, both pimavanserin and lumateperone have been approved by the FDA for the treatment of hallucinations and delusions associated with Parkinson's disease. In addition, they seems to be effective in treating schizophrenia to treat both positive AND negative symptoms. These drugs are currently under investigation for treating Bipolar Depression.


- Scott

 

Re: ritanserin, pimavanserin, and lumateperone SLS

Posted by undopaminergic on September 12, 2021, at 13:54:19

In reply to ritanserin, pimavanserin, and lumateperone undopaminergic, posted by SLS on September 12, 2021, at 12:52:04

> Hi, UD.

Hi SLS.

> > > Ritanserin is probably the most selective 5-HT2 antagonist in the world. When I looked in on it a bunch of years ago, it was reported to be virtually devoid of side effects. It is a drug without an indication. It has no other purpose that I recall other than being an antidepressant augmenter. By itself, it is inert.
> > >
> > >
> > > - Scott
>
>
> > But ritanserin is not clinically available as far as I know.
> >
> > -undopaminergic
>
>
>
> Exactly.

Right. But my question was about what is the best serotonin 5-HT2C antagonist that is clinically available.

I have previously encountered ritanserin, while reading neuroscientific research. It is very useful in researching the serotonergic system.

I would use it if I could acquire it readily. As it is now, I need something a doctor can prescribe.

>
> Ritanserin is a great drug without an indication. What clinical value does this drug have as monotherapy? None.
>

I'm not convinced of that, especially not if it is all that you say it is (ie. an *inverse* agonist). I would expect dose-dependent effects, including, possibly, a stimulant (inverse of apathy) effect.

> However it's possible that ritanserin would be a miracle augmenter of antidepressant treatment.
>

What I need it for is to block the apathy arising from the use of clomipramine or sertraline.

> Ritanserin acts as a "selective" ligand of:
>
> 1. 5-HT2a receptors (Ki = 0.45 nM)
> 2. 5-HT2c receptors (Ki = 0.71 nM).
>
> Ritanserin is labeled either a "selective" or "non-selective", depending on the authors of the available medical literature. At these receptors, ritanserin functions as an INVERSE AGONIST. An inverse agonist really acts as a super-antagonist. If a receptor is antagonized (blocked), it prevents the neuron from being stimulated in a neutral fashion. For example, let's say that the baseline level of neuron excitability in the absence of pharmacological intervention neuronal = 100 units. A pure antagonist might bring the excitability of the the neuron down = 0 units. Now, an "inverse agonist", when bound to the same receptor, will move the level of excitability to *below* the baseline = negative (-) 100. The inverse agonist actually suppresses the excitability of a neuron *below* its baseline. In a way, an inverse agonist actually causes a cell to do exactly the *opposite* of what an agonist does.
>

Yes. I did not know it was an inverse agonist.

> Although sometimes considered to be non-selective for all of the three subtypes of 5-HT2 receptors, Ritanserin really isn't. It does not bind to the 5-HT2b receptor subtype.
>

Wikipedia says it binds to other receptors too, including 5-HT2B, but does not report affinity values: https://en.wikipedia.org/wiki/Ritanserin

> There are three drugs other drugs that are supposed to be potent 5-HTa/c antagonists:
>
> 1. Pimavanserin
> 2. Roluperidone
> 3. Lumateperone.
>
> Unlike ritanserin, these drugs have other pharmacological properties. They aren't "clean". Of these, both pimavanserin and lumateperone have been approved by the FDA ...
>

Alas, they aren't approved in my locale (yet).

> ... for the treatment of hallucinations and delusions associated with Parkinson's disease. In addition, they seems to be effective in treating schizophrenia to treat both positive AND negative symptoms. These drugs are currently under investigation for treating Bipolar Depression.
>
>
> - Scott

You don't mention asenapine (Sycrest, Saphris). This is currently my main candidate.

-undopaminergic

 

Re: ritanserin, pimavanserin, and lumateperone undopaminergic

Posted by SLS on September 12, 2021, at 21:26:49

In reply to Re: ritanserin, pimavanserin, and lumateperone SLS, posted by undopaminergic on September 12, 2021, at 13:54:19

Hi again.


> You don't mention asenapine (Sycrest, Saphris). This is currently my main candidate.

I didn't know that about asenapine. Is it an inverse-agonist? I think you're looking at the right one, if for no other reason than I have seen it work long-term in a friend of mine to produce an improvement in both mood and cognition. However, she has schizoaffective disorder, bipolar-type. However, asenapine could not prevent the manic psychosis that she experienced as a reaction to Effexor. When I tried asenapine, I received a mild-moderate antidepressant effect that lasted for about a week before it capitulated to my supremely stubborn brain. I like asenapine. I found it to be a very clean drug with respect to side effects, including sedation or brain-fog.

I understand that most of the atypical antipsychotics are actually inverse-agonists of the 5-HT2a/c receptors. However, I read one paper that said specifically that asenapine was a pure antagonist and not an inverse agonist at 5-HT2a receptors with little affinity for 5-HT2c receptors. Asenapine causes virtually no weight gain compared to the great amount of weight gain with olanzapine and clozapine.

https://journals.sagepub.com/doi/10.1177/2045125311430112

"It is perhaps surprising that asenapine shares the high relative affinities at 5-HT2C and H1 receptors of clozapine and olanzapine yet avoids inducing the profound weight gain associated with these drugs; in bipolar patients asenapine showed a mean increase of 1.9kg vs 4.1kg with olanzapine over 12 weeks [McIntyre et al. 2009]. While effects on 5-HT1B and/or 5-HT1A receptors could conceivably contribute, asenapine administration demonstrates a notable lack of effect on 5-HT2C receptor density in rat brain [Tarazi et al. 2010]. This is similar to that of the weaker antagonists risperidone and quetiapine and is in contrast to the down-regulation seen with olanzapine [Tarazi et al. 2002]. The difference could conceivably relate to a 5-HT2C antagonism by asenapine in the absence of the inverse agonism exhibited by olanzapine and clozapine [Herrick-Davis et al. 2000] although this is untested; whatever the mechanism, it does indicate profoundly different pharmacological influences between asenapine and olanzapine on these important receptors involved in the control of body weight."

Good luck.


- Scott

 

Re: ritanserin, pimavanserin, and lumateperone SLS

Posted by undopaminergic on September 13, 2021, at 8:10:20

In reply to Re: ritanserin, pimavanserin, and lumateperone undopaminergic, posted by SLS on September 12, 2021, at 21:26:49

> Hi again.

Hi.

> > You don't mention asenapine (Sycrest, Saphris). This is currently my main candidate.
>
> I didn't know that about asenapine. Is it an inverse-agonist?

Antagonist I believe. According to my data, of all the numerous receptors it touches, it has the highest affinity for 5-HT2C.

> I think you're looking at the right one, if for no other reason than I have seen it work long-term in a friend of mine to produce an improvement in both mood and cognition.
>

Yes, you mentioned that in another post.

> However, she has schizoaffective disorder, bipolar-type.

I might have that too.

> However, asenapine could not prevent the manic psychosis that she experienced as a reaction to Effexor. When I tried asenapine, I received a mild-moderate antidepressant effect that lasted for about a week before it capitulated to my supremely stubborn brain. I like asenapine. I found it to be a very clean drug with respect to side effects, including sedation or brain-fog.
>

That is surprising, given how many receptor types it antagonises.

> I understand that most of the atypical antipsychotics are actually inverse-agonists of the 5-HT2a/c receptors.
>

I think they are mostly regular antagonists. Also, pretty much all of them have higher affinity for 5-HT2A than 5-HT2C.

Last time I checked, I only found one inverse agonist at 5-HT2C, and that was sertindole (Serdolect). I tried it and had to quit due to extreme nasal congestion.

> However, I read one paper that said specifically that asenapine was a pure antagonist and not an inverse agonist at 5-HT2a receptors with little affinity for 5-HT2c receptors. Asenapine causes virtually no weight gain compared to the great amount of weight gain with olanzapine and clozapine.
>

That is great. In any case, I've *lost* weight on clozapine.

>
> Good luck.
>

Thanks.

-undopaminergic

 

Re: ritanserin, pimavanserin, and lumateperone undopaminergic

Posted by SLS on September 13, 2021, at 14:52:09

In reply to Re: ritanserin, pimavanserin, and lumateperone SLS, posted by undopaminergic on September 13, 2021, at 8:10:20

Hi.

> Last time I checked, I only found one inverse agonist at 5-HT2C, and that was sertindole (Serdolect). I tried it and had to quit due to extreme nasal congestion.

Wasn't there a major problem with sertindole?

For me, nasal congestion is an effect that I am guessing is noradrenergic. Imipramine, desipramine, protriptyline, and a few others. I don't think it happened with amphetamines, but probably methylphenidate (Ritalin). Oh, it just occurred to me that the anticholinergic properties of the oral agents, like some TCAs, might cause it, too, but I'm not sure. Anticholinergics are used *topically* to treat congestion.

What did you think of Trintellix? It made me loopy, despite a couple of neurons firing in the beginning of treatment. Big brain-fog and a hint of derealization. However, I think it set up the brain for an almost tragic reaction to the subsequent switch to Effexor. I can't begin to describe how excruciating my reaction was, except to say that I had committed myself to give in to the inevitabilty of committing suicide when I arrived home from a trip to Minnesota to visit a friend of mine. I didn't dare do it in her house, so I decided to wait until I got home. I stopped the Effexor and was okay to travel in a few days. I have taken Effexor at least a handful of times with some benefit. Suicide never entered my mind while taking it.

Why do I go off on these tangents?

Sorry.


- Scott

 

Re: ritanserin, pimavanserin, and lumateperone SLS

Posted by undopaminergic on September 14, 2021, at 7:26:05

In reply to Re: ritanserin, pimavanserin, and lumateperone undopaminergic, posted by SLS on September 13, 2021, at 14:52:09

> Hi.

Hi.

> > Last time I checked, I only found one inverse agonist at 5-HT2C, and that was sertindole (Serdolect). I tried it and had to quit due to extreme nasal congestion.
>
> Wasn't there a major problem with sertindole?

Personally, I wouldn't call it major, but it can produce some QT-interval prolongation (more so than most other antipsychotics), which could be potentially lethal in a few particularly sensitive individuals. I had to take an ECG before starting it.

> For me, nasal congestion is an effect that I am guessing is noradrenergic. Imipramine, desipramine, protriptyline, and a few others. I don't think it happened with amphetamines, but probably methylphenidate (Ritalin). Oh, it just occurred to me that the anticholinergic properties of the oral agents, like some TCAs, might cause it, too, but I'm not sure. Anticholinergics are used *topically* to treat congestion.
>

Noradrenergic alpha-1 agonists are used in nasal decongestants (drops or spray). They cause blood vessels to constrict.

Other adrenergics, at least pseudoephedrine, are used orally for nasal congestion.

Anticholinergics are used topically (drops or sprays) to treat runny nose (rhinorrhea), not congestion directly.

> What did you think of Trintellix?

After the failure of lurasidone (which I'm still taking), I'm less interested in vortioxetine. Lurasidone is a high affinity serotonin 5-HT7 antagonist (vortioxetine is too; a bit lower affinity). However, unlike lurasidone, vortioxetine also antagonises serotonin 5-HT3 receptors, so it may still be worth a try, but first asenapine, and then maybe a switch from trimipramine to clomipramine. Clomipramine is probably the most powerful antidepressant that is not a MAOI.

> It made me loopy, despite a couple of neurons firing in the beginning of treatment. Big brain-fog ...
>

Isn't it supposed to do the opposite? (Treat cognitive impairment?)

> and a hint of derealization. However, I think it set up the brain for an almost tragic reaction to the subsequent switch to Effexor. I can't begin to describe how excruciating my reaction was, except to say that I had committed myself to give in to the inevitabilty of committing suicide when I arrived home from a trip to Minnesota to visit a friend of mine. I didn't dare do it in her house, so I decided to wait until I got home. I stopped the Effexor and was okay to travel in a few days. I have taken Effexor at least a handful of times with some benefit. Suicide never entered my mind while taking it.
>

Venlafaxine (Effexor) was a candidate among sertraline and clomipramine, but Dr. Gillman's writings have convinced me that I'm better off with clomipramine. He writes that sertraline is a stronger antagonist at the dopamine transporter than venlafaxine is at the noradrenaline transporter. His evidence for this is compelling, in particular the fact that venlafaxine does not attenuate the tyramine pressor effect.

> Why do I go off on these tangents?
>
> Sorry.

No problem.

-undopaminergic

 

Re: ritanserin, pimavanserin, and lumateperone undopaminergic

Posted by linkadge on September 19, 2021, at 16:10:43

In reply to Re: ritanserin, pimavanserin, and lumateperone SLS, posted by undopaminergic on September 14, 2021, at 7:26:05

>venlafaxine does not attenuate the tyramine >pressor effect.

I've heard that the in-vivo inhibition (by effexor) of the norepinephrine transporter is higher than would be indicated by traditional measures and may point to an alternative binding site for effexor towards the norepinephrine transporter.

I had hypertension on effexor at 75mg.

Linkadge

 

Re: ritanserin, pimavanserin, and lumateperone linkadge

Posted by SLS on September 19, 2021, at 17:15:04

In reply to Re: ritanserin, pimavanserin, and lumateperone undopaminergic, posted by linkadge on September 19, 2021, at 16:10:43

> >venlafaxine does not attenuate the tyramine >pressor effect.
>
> I've heard that the in-vivo inhibition (by effexor) of the norepinephrine transporter is higher than would be indicated by traditional measures and may point to an alternative binding site for effexor towards the norepinephrine transporter.

Do you know if desvenlafaxine (Prisiq) has markedly different effects on NE than the parent compound?


- Scott

 

Re: ritanserin, pimavanserin, and lumateperone

Posted by undopaminergic on September 20, 2021, at 8:20:30

In reply to Re: ritanserin, pimavanserin, and lumateperone undopaminergic, posted by linkadge on September 19, 2021, at 16:10:43

> >venlafaxine does not attenuate the tyramine >pressor effect.
>
> I've heard that the in-vivo inhibition (by effexor) of the norepinephrine transporter is higher than would be indicated by traditional measures ...
>

I've heard that too. But it sounds to me like it may be marketing.

> and may point to an alternative binding site for effexor towards the norepinephrine transporter.
>

If it inhibits the noradrenaline transporter through some alternative binding site, wouldn't it inhibit the tyramine pressor effect?

> I had hypertension on effexor at 75mg.
>

Could it be, for example, an imidazoline receptor antagonist?

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

Or could it be a metabolite?

-undopaminergic

 

Re: ritanserin, pimavanserin, and lumateperone

Posted by linkadge on September 21, 2021, at 18:01:57

In reply to Re: ritanserin, pimavanserin, and lumateperone linkadge, posted by SLS on September 19, 2021, at 17:15:04

>Do you know if desvenlafaxine (Prisiq) has >markedly different effects on NE than the parent >compound?

I don't think so. It has a slightly different ratio of SERT:NET but I think that's it. Although I don't think it's been extensively studied.

Linkadge

 

Re: ritanserin, pimavanserin, and lumateperone

Posted by linkadge on September 21, 2021, at 18:18:44

In reply to Re: ritanserin, pimavanserin, and lumateperone, posted by undopaminergic on September 20, 2021, at 8:20:30

>If it inhibits the noradrenaline transporter >through some alternative binding site, wouldn't it >inhibit the tyramine pressor effect?

From my understanding there are differences in the peripheral and central noradrenergic systems. Centrally, I think there are two versions of the norepinephrine transporter NET-1 and NET-2. Hypertension can be mediated centrally or peripherally or both. Also, not every NET inhibitor is equally potent at all sites in the brain. There may also be allosteric sites. Similar to serotonin reuptake, some of the SSRIs more potently inhibit SERT at certain sites vs. other sites. For example paroxetine and escitalopram don't bind to the exact same sites of the serotonin transporter. Escitalopram also binds to an allosteric site of the serotonin transporter (a secondary binding site).

Here's an in-vivo PET study (in primates) showing that effexor is essentially a 'balanced' SERT / NET inhibitor.

https://pubmed.ncbi.nlm.nih.gov/23090625/

 

A BIG thank you to Linkadge for his wealth of info

Posted by SLS on September 23, 2021, at 8:17:16

In reply to Re: ritanserin, pimavanserin, and lumateperone, posted by linkadge on September 21, 2021, at 18:18:44

.

 

Re: Best serotonin 5-HT2C antagonist?

Posted by Jay2112 on September 25, 2021, at 16:45:58

In reply to Re: Best serotonin 5-HT2C antagonist? SLS, posted by undopaminergic on September 12, 2021, at 8:30:01

> > Hi.
>
> Hi.
>
> > Ritanserin is probably the most selective 5-HT2 antagonist in the world. When I looked in on it a bunch of years ago, it was reported to be virtually devoid of side effects. It is a drug without an indication. It has no other purpose that I recall other than being an antidepressant augmenter. By itself, it is inert.
> >
> >
> > - Scott
>
> But ritanserin is not clinically available as far as I know.
>
> -undopaminergic

Nefadazone, available generically in the U.S.
has good 5ht2 antagonism. I found it a great drug to take possibly with an antipsychotic. Nefadazone does not feel *at all* like an SRI/SNRI.

Jay

 

Re: Best serotonin 5-HT2C antagonist? Jay2112

Posted by SLS on September 30, 2021, at 7:38:48

In reply to Re: Best serotonin 5-HT2C antagonist?, posted by Jay2112 on September 25, 2021, at 16:45:58

Hi, Jay.

> Nefadazone, available generically in the U.S.
> has good 5ht2 antagonism. I found it a great drug to take possibly with an antipsychotic. Nefadazone does not feel *at all* like an SRI/SNRI.


That's what others have said, too. I recall one person who responded only to nefazadone. She never remarked on any side effect that approached typical SSRI effects such as apathy, brain-fog, or amotivation.


- Scott


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