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Dr. Bob is Robert Hsiung, MD,
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Posted by linkadge on November 13, 2010, at 11:41:28
In reply to Vilazodone vs Nefazodone - 5-HT receptors, posted by Joe Schmoe on November 13, 2010, at 10:56:33
I think the sexual side effects mainly come from increased dopaminergic inhibition by serotonin.
Buspar has been known to alleviate sexual side effects from SSRIs. I believe the idea is that by preferentially activating the 5-ht1a autoreceptors it diminishes (or regulates) serotonin release in certain areas of the brain.
Essentually this in essense lowers activation of 5-ht2a/c receptors.Linkadge
Posted by ed_uk2010 on November 13, 2010, at 14:15:21
In reply to Vilazodone vs Nefazodone - 5-HT receptors, posted by Joe Schmoe on November 13, 2010, at 10:56:33
>I know some people have tried taking Buspirone for its effect on 5-HT1a for sexual side effects but I don't recall any rave reviews on the results.
I suspect that it sometimes helps but it's not used that often because it has side effects of its own.
Posted by SLS on November 14, 2010, at 3:11:26
In reply to Re: Vilazodone vs Nefazodone - 5-HT receptors, posted by ed_uk2010 on November 13, 2010, at 14:15:21
> >I know some people have tried taking Buspirone for its effect on 5-HT1a for sexual side effects but I don't recall any rave reviews on the results.
>
> I suspect that it sometimes helps but it's not used that often because it has side effects of its own.What about 5-HT2c blockade?
I found agomelatine to be somewhat pro-sexual. I am not sure what to attribute this to, though. It does stimulate M1 and M2 melatonin receptors. I was under the impression that it was the ability of agomelatine to block 5-HT2c serotonin receptors that was responsible for this effect.
Maybe Linkadge can offer an opinion as to what roles melatoninergic activation would play in the pro-sexual and antidepressant effects of agomelatine.
I might look into it later. Now, I have to shuttle my parents off to the airport. They are going to Aruba for two weeks. I would have gone with them, except that I knew I wouldn't enjoy myself. Maybe next year.
- Scott
Posted by bearfan on November 14, 2010, at 4:19:12
In reply to Re: Vilazodone vs Nefazodone - 5-HT receptors, posted by SLS on November 14, 2010, at 3:11:26
Anyone know a bit more about Vilazodone? Is this any kind of 'game-changer' as far as antidepressant treatment?
Posted by linkadge on November 14, 2010, at 7:56:17
In reply to Re: Vilazodone vs Nefazodone - 5-HT receptors, posted by SLS on November 14, 2010, at 3:11:26
>Maybe Linkadge can offer an opinion as to what >roles melatoninergic activation would play in >the pro-sexual and antidepressant effects of >agomelatine
I think I agree with you on the 5-ht2c thing. Animal studies seem to suggest that the combination of 5-ht2c antagonism and 5-ht2a *agonism* is prosexual.
However, there was one animal study I read which showed that melatonin administration was able to preserve the sexual activity of animals who were under stress.
Linkadge
Posted by linkadge on November 14, 2010, at 8:05:10
In reply to Re: Vilazodone vs Nefazodone - 5-HT receptors, posted by bearfan on November 14, 2010, at 4:19:12
>Anyone know a bit more about Vilazodone? Is this >any kind of 'game-changer' as far as >antidepressant treatment?
Some argue that the clinical efficacy of SSRI's is primarily due to 5-ht1a agonism. If this is the case, than agents more selective to this receptor could be more effective/selective.
From the profile, I would believe claims that the drug is potentially better for anxiety and/or reduced sexual dysfunction and/or insomnia.
Linkadge
Posted by SLS on November 14, 2010, at 8:54:20
In reply to Re: Vilazodone vs Nefazodone - 5-HT receptors, posted by linkadge on November 14, 2010, at 7:56:17
> >Maybe Linkadge can offer an opinion as to what >roles melatoninergic activation would play in >the pro-sexual and antidepressant effects of >agomelatine
>
> I think I agree with you on the 5-ht2c thing. Animal studies seem to suggest that the combination of 5-ht2c antagonism and 5-ht2a *agonism* is prosexual.
>
> However, there was one animal study I read which showed that melatonin administration was able to preserve the sexual activity of animals who were under stress.
>
>
> Linkadge
Thanks. I knew you'd come through!
- Scott
Posted by Joe Schmoe on November 14, 2010, at 11:49:14
In reply to Re: Vilazodone vs Nefazodone - 5-HT receptors » bearfan, posted by linkadge on November 14, 2010, at 8:05:10
> Some argue that the clinical efficacy of SSRI's is primarily due to 5-ht1a agonism. If this is the case, than agents more selective to this receptor could be more effective/selective.
>
> From the profile, I would believe claims that the drug is potentially better for anxiety and/or reduced sexual dysfunction and/or insomnia.
>
> Linkadge
Here is something interesting I ran across on another forum:"To clarify for those that don't really understand (as I didn't fully up until just a few days ago), these 5-HT1A partial agonists aren't actually enhancing 5-HT1A receptor activity at all, they're decreasing it by blocking/competing with serotonin -- a full agonist --, exclusvely at inhibitory 5-HT1A somatodendritic autoreceptors. This results in increased serotonin release and enhanced activity at 5-HT1A postsynaptic receptors. Note that these drugs have significantly higher affinity for somatodendritic autoreceptors over postsynaptic receptors, as receptors on the cell body and dendrites are much more accessible than those in synapses. Hence, at the low doses in which they're used, they inhibit autoreceptors with little actual action on postsynaptic receptors at all, resulting in therapeutic benefits."
http://www.socialanxietysupport.com/forum/f30/vilazodone-82779/#post1256448
I believe the drug company researching Vilazodone is claiming that this H-5T1a blockade of the somatic autoreceptors is what (somehow) leads to greater dopamine activity elsewhere.
Posted by linkadge on November 14, 2010, at 14:53:10
In reply to Re: Vilazodone vs Nefazodone - 5-HT receptors, posted by Joe Schmoe on November 14, 2010, at 11:49:14
>"To clarify for those that don't really >understand (as I didn't fully up until just a >few days ago), these 5-HT1A partial agonists >aren't actually enhancing 5-HT1A receptor >activity at all, they're decreasing it by >blocking/competing with serotonin -- a full >agonist --, exclusvely at inhibitory 5-HT1A >somatodendritic autoreceptors.
I don't know how accurate this is. For instance, buspar is a preferential autoreceptor agonist. Buspar has been shown to inhibit serotonin release upon acute administration (not enhance it as this guy suggests it would). However, over the long term, the drug would possibly desensitize the autoreceptor leading to enhanced serotonin release.
However, I think what is happening, is that people are morphing the mechanism of action into producing an effect that they have predetermined is "theraptutic". I might remind people that chronically stressing animals leads to a desensitization of the 5-ht1a autoreceptors. Serotonin can be highly anxiogenic, and I think that "control" of the autoreceptor function is more desirable than enhancing or inhibiting it.
Linkadge
Posted by Joe Schmoe on November 14, 2010, at 16:59:13
In reply to Re: Vilazodone vs Nefazodone - 5-HT receptors » Joe Schmoe, posted by linkadge on November 14, 2010, at 14:53:10
> >"To clarify for those that don't really >understand (as I didn't fully up until just a >few days ago), these 5-HT1A partial agonists >aren't actually enhancing 5-HT1A receptor >activity at all, they're decreasing it by >blocking/competing with serotonin -- a full >agonist --, exclusvely at inhibitory 5-HT1A >somatodendritic autoreceptors.
>
> I don't know how accurate this is. For instance, buspar is a preferential autoreceptor agonist. Buspar has been shown to inhibit serotonin release upon acute administration (not enhance it as this guy suggests it would).I actually don't see any disagreement between what you're saying and what he said. He said Vilazodone is a partial agonist and competes with serotonin (which is a full agonist) and effectively blocks 5-HT1a autoreceptors, which are inhibitory if stimulated, but Vilazodone keeps them from being stimulated, which allows synaptic serotonin to rise without any negative feedback mechanism from 5-HT1a. You're saying buspar, like serotonin, is a full agonist of 5-HT1a receptors and thus inhibits synaptic serotonin.
Either I'm misunderstanding what you are trying to say about buspar, or else it sounds to me like there is no disagreement between his statement and yours.
Why blockading 5-HT1a would reduce or eliminate sexual side effects is still unclear to me, especially if buspar achieves its pro-sexual effects by stimulating 5-HT1a instead of blockading it. If stimulation leads to desensitization eventually then maybe the end result is the same, higher synaptic serotonin levels, but why would that be pro-sexual?
Here is another link on the subject of partial agonists and 5-HT1a, citing language from studies of Vilazodone when it was still known as EMD 68843.
"vilazodone is also a partial agonist at 5-HT1A and has been shown to increase extracellular 5-HT levels to a higher degree than existing SSRIs..."
http://www.socialanxietysupport.com/forum/f30/vilazodone-82779/#post1251338
Posted by linkadge on November 14, 2010, at 17:42:45
In reply to Re: Vilazodone vs Nefazodone - 5-HT receptors, posted by Joe Schmoe on November 14, 2010, at 16:59:13
>He said Vilazodone is a partial agonist and >competes with serotonin (which is a full >agonist) and effectively blocks 5-HT1a >autoreceptors, which are inhibitory if >stimulated, but Vilazodone keeps them from being >stimulated, which allows synaptic serotonin to >rise without any negative feedback mechanism >from 5-HT1a.
I don't know if I agree with that. According to wikipedia, the way an agonist works depends on the amount of neurotransmitter already present:
"Clinically partial agonists can activate receptors to give a desired submaximal response when inadequate amounts of the endogenous ligand are present, or they can reduce the overstimulation of receptors when excess amounts of the endogenous ligand are present."
So I would disagree with the notion that an agonist is always going to behave functionally like an antagonist like this guy is saying.
>Why blockading 5-HT1a would reduce or eliminate >sexual side effects is still unclear to me, >especially if buspar achieves its pro-sexual >effects by stimulating 5-HT1a instead of >blockading it. If stimulation leads to >desensitization eventually then maybe the end >result is the same, higher synaptic serotonin >levels, but why would that be pro-sexual?
I don't think it is as simple as saying that buspar is always going to increase serotonin. Some studies show the opposite. Also buspar is confusing since its metabolites interact with norepinephrine and dopamine systems. A metabolite of buspar is a NE alpha-2 antagonist like the aphrodesiac yohimbine.
>"vilazodone is also a partial agonist at 5-HT1A >and has been shown to increase extracellular 5->HT levels to a higher degree than existing >SSRIs..."
Well I'd have to read the whole article to know what they're getting at here. I personally don't think that serotonin enhancement really has anything to do with the antidepressant effects of SSRI's. Heres a study which shows that chronic citalopram reduces serotonin function in the rat brain. Nobody really knows WTF is going on with these drugs.
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0006797
Posted by linkadge on November 14, 2010, at 17:46:19
In reply to Re: Vilazodone vs Nefazodone - 5-HT receptors, posted by Joe Schmoe on November 14, 2010, at 16:59:13
http://www.ncbi.nlm.nih.gov/pubmed/15978574
"In conclusion, we have demonstrated that vilazodone (100 nM, 1 microM), in the guinea-pig dorsal raphe nucleus, blocks the serotonin transporter but does not display 5-HT(1A) receptor agonism."
Linkadge
Posted by morgan miller on November 14, 2010, at 17:49:56
In reply to Re: Vilazodone vs Nefazodone - 5-HT receptors, posted by linkadge on November 14, 2010, at 17:42:45
>I personally don't think that serotonin enhancement really has anything to do with the antidepressant effects of SSRI's.
Wouldn't it make sense that serotonin enhancement has at least a part in the antidepressant effects of SSRIs, given that things like 5htp have such a pronounced antidepressant effect for many people?
Posted by linkadge on November 14, 2010, at 18:02:11
In reply to Re: Vilazodone vs Nefazodone - 5-HT receptors, posted by morgan miller on November 14, 2010, at 17:49:56
>Wouldn't it make sense that serotonin >enhancement has at least a part in the >antidepressant effects of SSRIs, given that >things like 5htp have such a pronounced >antidepressant effect for many people?
Where did I say that 5-htp does not have an antidepressant effect?
Linkadge
Posted by morgan miller on November 14, 2010, at 19:34:48
In reply to Re: Vilazodone vs Nefazodone - 5-HT receptors, posted by linkadge on November 14, 2010, at 18:02:11
> >Wouldn't it make sense that serotonin >enhancement has at least a part in the >antidepressant effects of SSRIs, given that >things like 5htp have such a pronounced >antidepressant effect for many people?
>
> Where did I say that 5-htp does not have an antidepressant effect?
>
> Linkadge
>Sorry, I guess I didn't make myself clear. Since SSRIs obviously have a significant impact on increasing the amount of serotonin in the brain, and other substances like 5htp that increase serotonin(I understand in a very different way than SSRIs) and don't have any other action that could explain their antidepressant effects, than wouldn't it make sense that the serotonin boosting effects of SSRIs are likely at least partially responsible for their antidepressant effect? Geeze, I think I just made it more confusing..Tired. Hopefully you understand what I'm trying to say here.
Posted by linkadge on November 14, 2010, at 20:12:24
In reply to Re: Vilazodone vs Nefazodone - 5-HT receptors, posted by morgan miller on November 14, 2010, at 19:34:48
>Sorry, I guess I didn't make myself clear. Since >SSRIs obviously have a significant impact on >increasing the amount of serotonin in the brain,
Necessarily not true. When given acutely maybe, but there are conflicting reports as to whether chronic administration of SSRIs actually increases serotonin neurotransmission. There are many compensatory changes that occur when SSRRIs are administered chronicaly.
According to wikipedia: "Certain SSRI medications have been shown to lower serotonin levels below the baseline after chronic use, despite initial increases in serotonin"
http://en.wikipedia.org/wiki/Serotonin
See the previous study I had posted above on citalopram:
"Citalopram administration caused a suppression of 5-HT synthesis at all time points. CIT treatment also caused a reduction in forebrain 5-HIAA content. Following chronic CIT treatment, forebrain 5-HT stores were more sensitive to the depleting effects of acute decarboxylase inhibition."
Also, the equlivlant or superior efficacy of tianeptine in anxious depression seems to argue against the low serotonin theory.
>and don't have any other action that could >explain their antidepressant effects,
B.S.
There are many other nonserotonergic targets of the SSRIs. Certain SSRIs like escitalopram have direct effects on adenylyl cyclase. SSRIs have been shown to exhibit anti-inflamatory and immune modulating effects independant of the serotonin reuptake inhibition. In addition other targets of the SSRIs include sigma receptors (sertraline, fluvoxamine), ion channels (calcium, sodium, potasium: trek-1) and monoamine receptors (fluoxetine), nitric oxide synthase and acetylcholine (paroxetine). In addition all of the SSRIs have been shown to dramatically increase the activity of the potent gabaergic neurosteroid allopregnanalone, a metabolite of progesterone which is low in depression. Interstingly remeron also increases the synthesis of allopregnanalone but it has no effect on the serotonin transporter. Some of the SSRIs have effects on ERK kinases, protein kinases as well as NMDA receptor function.
The SSRI antidepresants have this effect, but not any random agents with SERT binding. Many of these targets have shown antidepressant effects in animal models.
Linkadge
Posted by morgan miller on November 14, 2010, at 21:57:26
In reply to Re: Vilazodone vs Nefazodone - 5-HT receptors, posted by linkadge on November 14, 2010, at 20:12:24
>and don't have any other action that could >explain their antidepressant effects,
I knew my long winded sentenced would confuse things. I was talking about 5htp.
Posted by linkadge on November 15, 2010, at 5:46:25
In reply to Re: Vilazodone vs Nefazodone - 5-HT receptors, posted by morgan miller on November 14, 2010, at 21:57:26
>and don't have any other action that could >explain their antidepressant effects,
>I knew my long winded sentenced would confuse >things. I was talking about 5htp.
No you weren't. Otherwise you would have said "it" doesn't have any other action that could explain "its" antidepressant effects. Nice try though.
Linkadge
Posted by linkadge on November 15, 2010, at 5:56:29
In reply to Re: Vilazodone vs Nefazodone - 5-HT receptors, posted by morgan miller on November 14, 2010, at 19:34:48
Reading your previous post again, I can see what you were trying to say. However,
The action of SSRIs and of agents like 5-htp are very different. For instance, increasing serotonin levels using a precursor would also increase metabolic substances like N-acetyl-serotonin. This metabolite binds potently to the trk-a & trk-b receptors like BDNF and exerts potent antidepressant effects. However, an SSRI actually decreases the metabolism of serotonin and reduces the formation of this metabolite.
Also, serotonin is metabolised into melatonin. SSRIs however, in general, decrease the synthesis of melatonin. Some melatonergic agents have potent antidepressant effects in some people.
So there are two mechanisms of a serotonin precursor like 5-htp, which would not be shared by SSRIs.
Linkadge
Posted by SLS on November 15, 2010, at 6:05:10
In reply to Re: Vilazodone vs Nefazodone - 5-HT receptors, posted by linkadge on November 14, 2010, at 20:12:24
> Necessarily not true. When given acutely maybe, but there are conflicting reports as to whether chronic administration of SSRIs actually increases serotonin neurotransmission. There are many compensatory changes that occur when SSRRIs are administered chronicaly.
Yes. I was thinking that maybe a downregulation of presynaptic serotonin receptors in response to the dramatic and chronic increases in synaptic neurotransmitter would explain the increase in synthesis and, perhaps, release of serotonin. With the concentration of synaptic serotonin being kept artificially high, postsynaptic receptors will continue to be stimulated. The effect might be to increase synaptic serotonin acutely, but decrease the signal-to-noise ratio as the postsynaptic neuron remains partially depolarized. After chronic administration and the resulting reduction in postsynaptic receptor numbers, a new dynamic equilibrium is established, ultimately restoring or even enhancing the signal-to-noise ratio.
I am somewhat confused about all of this. There is so much more to be considered, as you demonstrated better than I could. I have always wondered if pushing the system in either direction causes a reset of the homeostatic "thermostat" to a new equilibrium that more closely resembles a normal dynamic. This notion might explain the effectiveness of both serotonin reuptake inhibitors (fluoxetine) and reuptake enhancers (tianeptine).
> According to wikipedia: "Certain SSRI medications have been shown to lower serotonin levels below the baseline after chronic use, despite initial increases in serotonin"
Okay. now I'm really confused.
http://molpharm.aspetjournals.org/content/61/4/778.short
"Up-Regulation of Tryptophan Hydroxylase Expression and Serotonin Synthesis by Sertraline"
Oh, well.
- Scott
Posted by iforgotmypassword on November 15, 2010, at 16:42:17
In reply to Re: Vilazodone vs Nefazodone - 5-HT receptors, posted by SLS on November 15, 2010, at 6:05:10
this is much more than another ssri somehow making it to market should be treated with due scepticism. last i remember effects beyond being simply an SSRI were not proven in vivo, and did not prove to have the effect of an 5-ht1a agonist in any practical sense.
Posted by linkadge on November 15, 2010, at 17:23:31
In reply to Re: Vilazodone vs Nefazodone - 5-HT receptors, posted by SLS on November 15, 2010, at 6:05:10
>Okay. now I'm really confused.
>http://molpharm.aspetjournals.org/content/61/4/77>8.short
>"Up-Regulation of Tryptophan Hydroxylase >Expression and Serotonin Synthesis by Sertraline"
This probably explains why one person responds to a particular SSRI and not another. They're not interchangeable
Linkadge
Posted by Joe Schmoe on November 15, 2010, at 17:30:53
In reply to Re: Vilazodone vs Nefazodone - 5-HT receptors » SLS, posted by linkadge on November 15, 2010, at 17:23:31
Reminds me of something I just read on Wikipedia:
"The recent research suggests that a significant part of the resistance to the SSRIs paroxetine (Paxil) and citalopram (Celexa) can be explained by the genetic variation of Pgp transporter. Paroxetine and citalopram, which are Pgp substrates, are actively transported from the brain by this protein."
Posted by morgan miller on November 15, 2010, at 19:41:28
In reply to Re: my appologies, posted by linkadge on November 15, 2010, at 5:56:29
No big deal man. I was in a hurting state of mind and should not have been posting thoughts on things like that.
Posted by morgan miller on November 15, 2010, at 19:45:09
In reply to Re: Vilazodone vs Nefazodone - 5-HT receptors, posted by SLS on November 15, 2010, at 6:05:10
> According to wikipedia: "Certain SSRI medications have been shown to lower serotonin levels below the baseline after chronic use, despite initial increases in serotonin"
What SSRIs? Citalopram I'm guessing is one. This reaction may also be dependent on individual brain chemistry/function.
This is the end of the thread.
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