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Dr. Bob is Robert Hsiung, MD,
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Posted by jparsell82 on September 3, 2009, at 14:25:56
In reply to D2 And 5HT2A: Dopamine Blocking And Boosting, posted by Brainbeard on July 17, 2009, at 5:32:24
And what ever happened to Ritanserin? I remember reading before that it was pretty selective for 5-ht2 and had shown anxiolytic and antidepressant effects.
Posted by Brainbeard on September 4, 2009, at 2:05:25
In reply to Re: D2 And 5HT2A: Dopamine Blocking And Boosting, posted by jparsell82 on September 3, 2009, at 14:17:14
> How about Trazodone?
Too sedative.
Posted by Brainbeard on September 4, 2009, at 2:09:25
In reply to Re: D2 And 5HT2A: Dopamine Blocking And Boosting, posted by jparsell82 on September 3, 2009, at 14:25:56
> And what ever happened to Ritanserin? I remember reading before that it was pretty selective for 5-ht2 and had shown anxiolytic and antidepressant effects.
I've tried finding a source on the internet, to no avail.
I find it creepy that ritanserin is known to inhibit blood platelet function, thereby increasing the risk of abnormal bleeding. (S)SRIs do that too. I wonder if any 5HT2-antagonist would decrease blood platelet function, or it is something specific to ritanserin. If not, combining an SSRI with a 5HT2A-antagonist might increase the risk of abnormal bleeding more than an SSRI alone. I wouldn't be comfortable with that.
Posted by g_g_g_unit on October 3, 2009, at 23:59:36
In reply to Re: D2 And 5HT2A: Dopamine Blocking And Boosting, posted by Brainbeard on September 4, 2009, at 2:09:25
were you taking the Risperdal at night? my pdoc prescribed 0.25-0.5mg for OCD, and instructed i take it before bed. forgive my naivete, but i thought the dopamine boosting at that dose might produce insomnia if taken at night?
the originally plan was to taper off Parnate, and start taking Anafranil with Risperdal, but i've decided to continue with Parnate instead. i'm interested in testing out the Risperdal though, for the benefits you noted here.
Posted by Brainbeard on October 4, 2009, at 6:40:12
In reply to hey brainbeard, posted by g_g_g_unit on October 3, 2009, at 23:59:36
Oh, I certainly took the Risperdal at night. Though I had some insomnia while starting up, eventually I slept like a log, as can be expected when taking a potent 5HT2A-antagonist.
Posted by g_g_g_unit on October 5, 2009, at 18:18:02
In reply to Re: hey brainbeard » g_g_g_unit, posted by Brainbeard on October 4, 2009, at 6:40:12
> Oh, I certainly took the Risperdal at night. Though I had some insomnia while starting up, eventually I slept like a log, as can be expected when taking a potent 5HT2A-antagonist.
>you said you stopped taking it due to its effect on prolactin? are there dangers present even at such a low dosage? i asked my psych, but obviously he said the drug was harmless...
Posted by Brainbeard on October 6, 2009, at 16:08:56
In reply to Re: hey brainbeard, posted by g_g_g_unit on October 5, 2009, at 18:18:02
>
> you said you stopped taking it due to its effect on prolactin? are there dangers present even at such a low dosage? i asked my psych, but obviously he said the drug was harmless...Did he now? Well, either he's lying or he doesn't know what he's talking about (which may be even worse). From a 2006 study: 'Even low doses of risperidone used as an augmentation to antidepressants or benzodiazepines are associated with hyperprolactinemia and can induce endocrinological side effects.' (http://cat.inist.fr/?aModele=afficheN&cpsidt=18605450) This study included 0.5mg doses.
Hyperprolactinemia (very high levels of prolactin) in turn can cause pituitary tumors, and guess what? - risperdal has been linked with those, although the validity of the link has been debated (as might be expected with such a succesful antipsychotic).
Posted by g_g_g_unit on October 8, 2009, at 5:03:44
In reply to Re: hey brainbeard, posted by Brainbeard on October 6, 2009, at 16:08:56
> Did he now? Well, either he's lying or he doesn't know what he's talking about (which may be even worse). From a 2006 study: 'Even low doses of risperidone used as an augmentation to antidepressants or benzodiazepines are associated with hyperprolactinemia and can induce endocrinological side effects.' (http://cat.inist.fr/?aModele=afficheN&cpsidt=18605450) This study included 0.5mg doses.
>
> Hyperprolactinemia (very high levels of prolactin) in turn can cause pituitary tumors, and guess what? - risperdal has been linked with those, although the validity of the link has been debated (as might be expected with such a succesful antipsychotic).
>yeah, somehow it would be more comforting to think that psychiatrists' complete faith in psychotropics was the result of willful misguidance rather than delusion. i guess that their logic dictates that treating the 'disease' compensates for any collateral damage incurred, though i don't believe there's any excuse for not warning the patient about potential metabolic damage. i think i'll avoid Risperdal for the time being; when combined with Parnate, even the dopamine rebound (i'm guessing?) from 25mg of Seroquel was enough to cause some noticeable agitation the following day.
Posted by conundrum on February 22, 2010, at 10:00:20
In reply to D2 And 5HT2A: Dopamine Blocking And Boosting, posted by Brainbeard on July 17, 2009, at 5:32:24
>Stahl also says somewhere that D2-antagonism may be necessary for the pro-dopaminergic effects of .5HT2A-antagonism.
>What remains to be sorted out for me is what D2-antagonism actually entails and which parts of the brain are involved.
The following abstract may answer some of these questions. It seems that antagonizing the 5 HT2A may not lead to the dopaminergic pot of gold since it can reduce DA release in the Nucleus accumbens, but increases it in the medial prefrontal cortex. It also does nothing on its own to potentiate dopamine release. This could explain why trazodone isn't a very powerful antidepressant despite its strong 5 HT2A blockade. Nefazodone isn't much better and needs to be taken at a much higher concentration aroudn 300-600mgs to begin to engage the serotonin transporters.
"5-HT2A receptor antagonism potentiates haloperidol-induced dopamine release in rat medial prefrontal cortex and inhibits that in the nucleus accumbens in a dose-dependent manner
Abstract
Combined serotonin (5-HT)2A and dopamine (DA) D2 blockade has been shown to contribute to the ability of atypical antipsychotic drugs (APDs) to increase DA release in rat medial prefrontal cortex (mPFC). We provide additional support for this hypothesis by examining the effect of the selective 5-HT2A antagonist M100907 plus haloperidol, a potent D2 antagonist APD, on DA release in the mPFC and nucleus accumbens (NAC). Haloperidol (0.01–1.0 mg/kg) produced an inverted U-shaped increase in DA release in the mPFC, with a significant increase only at 0.1 mg/kg. Haloperidol (0.1 and 1.0 mg/kg) significantly increased DA release in the NAC.
****M100907 [5 HT2A antagonist](0.1 mg/kg) by itself had no effect on DA release in either region. ******This dose of M100907 potentiated the ability of low (0.01–0.1 mg/kg), but not high dose (0.3–1.0 mg/kg) haloperidol to increase mPFC DA release, whereas it abolished the effect of both 0.1 and 1.0 mg/kg haloperidol on NAC DA release. These results suggest that the relatively higher ratio of 5-HT2A to D2 antagonism may contribute to the potentiation of haloperidol-induced mPFC DA release, whereas 5-HT2A antagonism can diminish haloperidol-induced NAC DA release, even when combined with extensive D2 antagonism, which may not be synergistic with 5-HT2A antagonism in the mPFC."
Also I found another study showing that 5-HT2A antagonism blocks the release of dopamine in response to amphetamine in the Nucleus Accumbens and the striatum. However a 5-HT2B/C antagonist potentiates its release in response to morphine.
I'm just gonna post the link to that one:
http://www.nature.com/npp/journal/v26/n3/abs/1395776a.html
I wonder what the effects of these receptors is on NA release?
Posted by Brainbeard on February 22, 2010, at 13:15:03
In reply to Re: D2 And 5HT2A: Dopamine Blocking And Boosting » Brainbeard, posted by conundrum on February 22, 2010, at 10:00:20
Interesting stuff.
Posted by conundrum on February 22, 2010, at 22:47:28
In reply to Re: D2 And 5HT2A: Dopamine Blocking And Boosting, posted by Brainbeard on February 22, 2010, at 13:15:03
This could also explain why prozac increases DA in the cortex but not in the NAc, if the Lilly study I posted is accurate and fluoxetine is a 5 ht2a antagonist.
This stuff is getting too confusing it seems. Is 5 HT2a attenuation of amphetamine dopaminergic release an accurate display of its actions? Usually those transporters aren't working in reverse.
Found another study showing that a 5 HT2A antagonist has antipsychotic properties but none for depression or anxiety.
http://jpet.aspetjournals.org/content/277/2/968.abstract?ref=Sawos.Org
However, another study shows that chronic treatment with an experimental SRI with 2A antagonistic properties prevents the decrease in NE normally associated with SRI use. See below.
http://jpet.aspetjournals.org/content/302/3/983.abstract
Then this study shows the same drug increases NE extracellular levels in the PFC.
http://dx.doi.org/10.1016/S0014-2999(00)00173-4
More confusion ensues regarding effects in other parts of the brain...hypothalmus 5 ht2a antagonist decreases NE levels here preventing hyperthermia.
http://www.ncbi.nlm.nih.gov/pubmed/11164765
Add to this mess that I've heard that 5HT2A/C receptors don't downregulate like other receptors and only down regulate when antagonized. (don't know if thats true or not).
So apparently this just got really confusing. Fully elucidating which antagonist do what is hard to say. None of this stuff occurs in a vacuum. In the end trying to understand it may be a waste of time. Drug trials may be less nerve wracking then trying to go the scientific route, especially when you don't fully understand everything in the studies, when you don't understand how the brain regions work together, when you don't know if the data was cooked up by a drug company.
Posted by Brainbeard on February 23, 2010, at 9:07:11
In reply to Re: D2 And 5HT2A: Dopamine Blocking And Boosting » Brainbeard, posted by conundrum on February 22, 2010, at 22:47:28
> This could also explain why prozac increases DA in the cortex but not in the NAc, if the Lilly study I posted is accurate and fluoxetine is a 5 ht2a antagonist.
Yeah, but don't forget Prozac is a more potent 5HT2C-antagonist.
> This stuff is getting too confusing it seems.My idea too.
> However, another study shows that chronic treatment with an experimental SRI with 2A antagonistic properties prevents the decrease in NE normally associated with SRI use.Yes, I've seen a study showing the same for Risperdal augmentation of SSRI treatment.
> Add to this mess that I've heard that 5HT2A/C receptors don't downregulate like other receptors and only down regulate when antagonized. (don't know if thats true or not).
No, 5HT2A/C receptors downregulate throught the SSRI's indirect agonism also. It's strange, downregulation of 5HT2C-receptors at least would mediate enhanced dopaminergic functioning, as well as weight gain, but with SSRI's our picture isn't exactly one of enhanced dopaminergic functioning, althoug the weight gain does show up usually to be sure. Personally, SSRI's stimulate pleasure seeking behavior in me and tend to make me hypersexual MENTALLY, which may be symptoms of 5HT2C downregulation.
> So apparently this just got really confusing.Right.
>None of this stuff occurs in a vacuum. In the end trying to understand it may be a waste of time.
So true.
>Drug trials may be less nerve wracking then trying to go the scientific route (.....)Yeah, and how about combining hypotheses based on science with thorough experimentation? That's what I try to do, though not all of my doctors appreciate it as much.. ;)
Posted by Brainbeard on February 23, 2010, at 9:09:16
In reply to Re: D2 And 5HT2A: Dopamine Blocking And Boosting » Brainbeard, posted by conundrum on February 22, 2010, at 22:47:28
See this thread for an explanation of how Prozac is an effective 5HT2C-antagonist, at least in lower doses: http://www.dr-bob.org/cgi-bin/pb/mget.pl?post=/babble/neuro/20091104/msgs/931609.html#931609
Posted by conundrum on February 23, 2010, at 13:56:46
In reply to Re: D2 And 5HT2A: Dopamine Blocking And Boosting, posted by Brainbeard on February 23, 2010, at 9:07:11
>Yeah, but don't forget Prozac is a more potent 5HT2C-antagonist.
That would seem to be so, since its more activating and the least sleep promoting of the SSRIs. The Lilly study I posted showed that Prozac has a similar potency for both types of 5-HT2 receptors. 119 ± 10 for 2A and 118 ± 11 for 2C. Its interesting that no other studies even mention the 5 HT2A antagonism. Is this just something else that Lilly cooked up like when they hid suicidal ideation caused by the drug or the metabolic problems with Zyprexa?
Also, The study linked below uses Ki 5 and not just Ki, I guess this is the same potency but just at a different scale or is the data just different? In the PNAS article the Ki is much weaker at the 5 HT pump than the Lilly study and stronger as a 5 HT2C antagonist.
http://www.pnas.org/content/94/5/2036.full.pdf>No, 5HT2A/C receptors downregulate throught the SSRI's indirect agonism also. It's strange, downregulation of 5HT2C-receptors at least would mediate enhanced dopaminergic functioning, as well as weight gain, but with SSRI's our picture isn't exactly one of enhanced dopaminergic functioning, althoug the weight gain does show up usually to be sure. Personally, SSRI's stimulate pleasure seeking behavior in me and tend to make me hypersexual MENTALLY, which may be symptoms of 5HT2C downregulation.
Even though downregulation occurs with SSRIs I imagine only an antagonist would significantly increase DA/NE release. After all you are still activating those downregulated receptors with an SSRI even if there are less of them and they are desensitized. Did you notice any difference between prozac and other SSRIs? I've noticed the lexapro makes everything limp and not just between my legs. It makes me tired and slows my thinking down. Prozac is kinda similar at higher doses. I've noticed an increase in motivation and possibily hedonia after about month of taking 5mg every other day. I wonder how low I can go and still get an effect? Did you notice any activating effects of prozac immediately? I don't. It seems that 5 HT receptors need about a month to become downregulated in order to increase NE/DA OR that NE/DA are increased immediately and that those systems need to adapt. Then there is the whole waiting 29 days to reach a steady state problem.
If what I really need is NE this is a hell of a way to get it. A tricyclic might be a better route.
One of the main problems with these studies is some seem to say at a higher dose NE/DA is boosted, like if you look at the Lilly study where they found 3mg/kg didn't have much of an effect but 30mg/kg had increase NE more than SER However the one you posted here seems to say the opposite:
http://www.pnas.org/content/94/5/2036.full.pdfAlso how do these doses compare to humans? 3 mg/kg seems like a lot if you ask me, but rats metabolize quickly.
Do you have any resources for explaining IC 50 and Ki and all that stuff?
>Yeah, and how about combining hypotheses based on science with thorough experimentation? That's what I try to do, though not all of my doctors appreciate it as much.. ;)
Pdoc said I have an obsessive disorder for trying to solve this problem scientifically, not an affective disorder. He said its like throwing darts on a board and seeing what works. I just don't want to waste my time taking drugs that may not work or could have horrible withdrawals. So far the only dart that has had any benefit was low dose prozac with buspar, and thats something that I thought out here thanks to your posts.
Posted by Brainbeard on February 24, 2010, at 3:42:35
In reply to Re: D2 And 5HT2A: Dopamine Blocking And Boosting » Brainbeard, posted by conundrum on February 23, 2010, at 13:56:46
There does seem to be a huge difference between indirect agonism (SSRI's) and direct antagonism of serotonin subtype receptors (5HT2A/C).
I haven't taken Prozac in normal doses, only low doses, so I can't evaluate the difference between Prozac and the other SSRI's.
For me, the mood-lifting and stimulating effects of low dose Prozac do indeed seem to occur immediately, as long as I don't go higher than 5mg a day.
For me, the noradrenergic boost of 25mg of imipramine can make an immediate difference. Imipramine's metabolite desipramine is a strong NRI, but in Holland it isn't available anymore, while it's also nearly impossible to buy it over the internet without a prescription.
I honestly have no clue as to how rat doses compare to human doses.
I don't have the time to find about about the different Ki values.I have been diagnosed as an obsessive med tweaker too. It can make it harder to get meds prescribed. My current doc, a family doc, is against polypharmacy. I have objected to this that many medications, like the TCA's and the new generations antipsychotics, have manifold pharmacological actions in one pill. He had to agree to that.
Oh, one very important point: Stahl has argued that either 5HT2A or -C-antagonism, or SRI, or 5HT1A-agonism IN THEMSELVES might not have much therapeutic value, but that it's the SYNERGY between these pharmacological mechanisms that makes for the antidepressant efficacy.
Posted by yasser on March 13, 2010, at 14:17:38
In reply to D2 And 5HT2A: Dopamine Blocking And Boosting, posted by Brainbeard on July 17, 2009, at 5:32:24
ok !! i m personally taking mirtazapine (high dose) with reboxetine and selegiline (low dose). i also take some 5-htp .
thus i m attacking all monoamines with antagonising dirty receptors.mirtazapine (remeron) eliminate dirty receptors (5HT2c and 5HT2a ) and also alpha2 adreno receptor that you forgot to mention . blockade of alphaa adrenoreceptor have been shown to enhance the all 3 monoamines activity.
high synaptic level of norepinephrine (the result of alpha2 and norepinephrine reuptake inhibition by reboxetine ) accelerate dopamine and 5ht activity by stimulating alpha1 adrenoreceptors located in dopamine and 5ht cell body.
and selegiline for his cathecholamine and anti aging (ngf bdnf ....) enhancing effect in general and his prodopamine effect by his maoi b activity.
another combinaison is to take mirtazapine (high dose) with bupropion (wellbutrin), assuring a 5ht and norepinephrine and dopamine boosting effect and eliminating dirty receptors 5ht2a 5ht2c and α2.
Posted by conundrum on March 13, 2010, at 15:59:30
In reply to Re: D2 And 5HT2A: Dopamine Blocking And Boosting, posted by yasser on March 13, 2010, at 14:17:38
But does your combo work?
Posted by Brainbeard on March 13, 2010, at 17:21:25
In reply to Re: D2 And 5HT2A: Dopamine Blocking And Boosting, posted by yasser on March 13, 2010, at 14:17:38
Haha Conundrum, I was wondering about that too.
Yasser, let me ask this straight: aren't you fat and drowsy?
Posted by yasser on March 13, 2010, at 23:01:36
In reply to Re: D2 And 5HT2A: Dopamine Blocking And Boosting, posted by yasser on March 13, 2010, at 14:17:38
hahaha!! yes it works very well ! drowsy the first week yess !!! fat no .
i tried a lot of combos in the past that one seems to be the best for me , but every one respond differently .
Posted by conundrum on March 14, 2010, at 7:09:23
In reply to Re: D2 And 5HT2A: Dopamine Blocking And Boosting, posted by yasser on March 13, 2010, at 23:01:36
How much 5 HTP are you using? That stuff knocked me out when i tried it. Then I read that people only need a quarter of a capsule.
Posted by yasser on March 14, 2010, at 16:31:37
In reply to Re: D2 And 5HT2A: Dopamine Blocking And Boosting, posted by yasser on March 13, 2010, at 23:01:36
i don t use 5 htp regulary, i specially take it when i feel nervous and irritable or when i feel the beginning of migrain (i m migrainous since i have 7 years old (im 23 now) ). i take 2 capsule of 50 mg each for migrain or just one every other day.
surely it calm me down and give a good mental ease and serenity (or sleepiness) .thus i take it when i finish my day and just need some tranquility before the remeron knock me out.
Posted by g_g_g_unit on July 16, 2010, at 4:56:34
In reply to Re: D2 And 5HT2A: Dopamine Blocking And Boosting, posted by Brainbeard on February 23, 2010, at 9:07:11
stupid question maybe but how would taking an SSRI + low-dose AAP differ from taking Prozac?
Posted by Conundrum on July 16, 2010, at 18:49:24
In reply to Re: D2 And 5HT2A: Dopamine Blocking And Boosting, posted by g_g_g_unit on July 16, 2010, at 4:56:34
With the exception of Zyprexa there would be more 5HT2A antagonism than with prozac. So it would probably have less sexual dysfunction. Also There would be increased dopamine release via D2 autoreceptors being blocked. When dopamine binds to an autoreceptor it tells the nerve to stop producing dopamine. By blocking them or being a reverse agonist it increases the release of dopamine. Prozac doesn't do that. Prozac only blocks 5HT2C and according to one study from Eli Lilly, 5 HT2A receptors. It also depends on the AAP. Amulsipride doesn't touch serotonergic receptors. Seroquel is a norepinephrine reuptake inhibitor.
Basically You'd get more dopamine if you kept the dose really low.
Posted by g_g_g_unit on July 16, 2010, at 23:41:43
In reply to Re: D2 And 5HT2A: Dopamine Blocking And Boosting » g_g_g_unit, posted by Conundrum on July 16, 2010, at 18:49:24
> With the exception of Zyprexa there would be more 5HT2A antagonism than with prozac. So it would probably have less sexual dysfunction. Also There would be increased dopamine release via D2 autoreceptors being blocked. When dopamine binds to an autoreceptor it tells the nerve to stop producing dopamine. By blocking them or being a reverse agonist it increases the release of dopamine. Prozac doesn't do that. Prozac only blocks 5HT2C and according to one study from Eli Lilly, 5 HT2A receptors. It also depends on the AAP. Amulsipride doesn't touch serotonergic receptors. Seroquel is a norepinephrine reuptake inhibitor.
>
> Basically You'd get more dopamine if you kept the dose really low.hmm, i wonder how significant the effect would be, or if it would just get buried under the serotonin reuptake. i've been thinking about trying brainbeard's proposed zoloft + low-dose geodon combo.
Posted by Conundrum on July 17, 2010, at 0:18:43
In reply to Re: D2 And 5HT2A: Dopamine Blocking And Boosting » Conundrum, posted by g_g_g_unit on July 16, 2010, at 23:41:43
Its just one of those things, you don't know until you try.
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Dr. Bob is Robert Hsiung, MD,
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