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Dr. Bob is Robert Hsiung, MD,
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Posted by SLS on December 3, 2010, at 6:52:24
In reply to Doxepin binding data?, posted by psychobot5000 on December 3, 2010, at 0:03:23
> Hi,
>
> Can anyone tell me where to find the binding affinities of doxepin? I'm trying to figure out how its 5ht-2a binding compares to H1, as well as 5ht-2c--H1 and 5ht2a seem to be helpful to me (though not necessarily at the same time), while 2c is counterproductive. I just started some tiny doses of doxepin, and I'm trying to figure out how it works and how to dose it. I'd be curious to see data for other tricyclics, too, but that's a digression.
>
> Thanks,
> Psychbot
>
> PS - Haven't been here in a while--hope you are all well.This is a great database for looking up binding affinities. You will want to enter the name of the drug in the "Test Ligand" box.
http://pdsp.med.unc.edu/pdsp.php
- Scott
Posted by Conundrum on December 3, 2010, at 11:50:50
In reply to Doxepin binding data?, posted by psychobot5000 on December 3, 2010, at 0:03:23
if you trust wikipedia:
http://en.wikipedia.org/wiki/Tricyclic_antidepressantthere is a table at the bottom with the binding data for most of the commonly used TCAs.
> Hi,
>
> Can anyone tell me where to find the binding affinities of doxepin? I'm trying to figure out how its 5ht-2a binding compares to H1, as well as 5ht-2c--H1 and 5ht2a seem to be helpful to me (though not necessarily at the same time), while 2c is counterproductive. I just started some tiny doses of doxepin, and I'm trying to figure out how it works and how to dose it. I'd be curious to see data for other tricyclics, too, but that's a digression.
>
> Thanks,
> Psychbot
>
> PS - Haven't been here in a while--hope you are all well.
Posted by linkadge on December 4, 2010, at 19:51:21
In reply to Re: Doxepin binding data?, posted by Conundrum on December 3, 2010, at 11:50:50
Doxapin is a pretty good med IMHO. I kind of liked it better than amitriptyline, but I was scared about the genotoxicity.
Linkadge
Posted by psychobot5000 on December 5, 2010, at 10:18:55
In reply to Re: Doxepin binding data?, posted by linkadge on December 4, 2010, at 19:51:21
Hmm. Didn't know about the genotoxicity...
Otherwise, thanks all--I'd tried to use the PDSP database, but my lack of knowledge of appropriate terminology prevented me from using it effectively. Now I seem to be able to get it to work. The Wikipedia page is also useful.
Unfortunately, it doesn't include 5ht2c binding. Anyone know which TCAs have stronger binding at 2a than 2c, or how trimipramine fairs in this regard? (PDSP doesn't come up with much for trimipramine)
Posted by linkadge on December 5, 2010, at 11:52:55
In reply to Re: Doxepin binding data?, posted by psychobot5000 on December 5, 2010, at 10:18:55
I think clomipramine is stronger at 2a than 2c, but I could be wrong.
Linkadge
Posted by ed_uk2010 on December 5, 2010, at 18:31:21
In reply to Re: Doxepin binding data?, posted by linkadge on December 5, 2010, at 11:52:55
Doxepin is great if you want an antihistamine.
Posted by psychobot5000 on December 5, 2010, at 19:42:50
In reply to Re: Doxepin binding data?, posted by ed_uk2010 on December 5, 2010, at 18:31:21
> Doxepin is great if you want an antihistamine.
Yeah, I'm finding this is the case--but I'm finding I have to dose it -really- low (not sure yet how low...it's sort of hard to figure out), i.e. 3mg, in order to get that benefit without the other psychotropic stuff...
Posted by ed_uk2010 on December 6, 2010, at 13:23:07
In reply to Re: Doxepin binding data? » ed_uk2010, posted by psychobot5000 on December 5, 2010, at 19:42:50
> > Doxepin is great if you want an antihistamine.
>
> Yeah, I'm finding this is the case--but I'm finding I have to dose it -really- low (not sure yet how low...it's sort of hard to figure out), i.e. 3mg, in order to get that benefit without the other psychotropic stuff...Really low doses are supposed to be good for chronic insomnia.
Posted by sigismund on December 6, 2010, at 13:59:01
In reply to Re: Doxepin binding data?, posted by ed_uk2010 on December 6, 2010, at 13:23:07
>Really low doses are supposed to be good for chronic insomnia.
I've got some here. What's the dose for insomnia? I think the caps I have are 10mg. It is an antihistamine type effect, as I recall. i didn't like it as much as Avanza (while I was asleep) but after Avanza I was a wreck until 3pm. Now if they would Rx amphetmine with Avanza.......
The agomelatine melatonin action wears off (doesn't work any more on me) but the 5ht2c thing is durable.
Posted by ed_uk2010 on December 6, 2010, at 14:59:18
In reply to Re: Doxepin binding data? » ed_uk2010, posted by sigismund on December 6, 2010, at 13:59:01
>I've got some here. What's the dose for insomnia? I think the caps I have are 10mg.
Try half a capsule (I know it's not convenient to split capsules!)
>Now if they would Rx amphetmine with Avanza.......
That's what you need Sigi. A downer then an upper. Very 1960s :)
Posted by psychobot5000 on December 6, 2010, at 22:09:05
In reply to Re: Doxepin binding data? » sigismund, posted by ed_uk2010 on December 6, 2010, at 14:59:18
> >I've got some here. What's the dose for insomnia? I think the caps I have are 10mg.
>
> Try half a capsule (I know it's not convenient to split capsules!)
>
> >Now if they would Rx amphetmine with Avanza.......
>
> That's what you need Sigi. A downer then an upper. Very 1960s :)According to wikipedia, the doses for insomnia are 3mg and 6mg--so splitting that capsule would put you right in the high-middle of that range (though I'm finding that the lower end may work better)
Posted by sigismund on December 7, 2010, at 1:27:17
In reply to Re: Doxepin binding data? )) Sigismund, posted by psychobot5000 on December 6, 2010, at 22:09:05
>(though I'm finding that the lower end may work better)
I remember not liking doxepin.
I actually preferred mirtazepine (until I got up), perhaps because it deepened sleep.
Then I had to wait until 3pm to feel that the poison had left my system.Doxepin did not seem to deepen sleep in the same way, IIRC.
Posted by sigismund on December 7, 2010, at 1:29:11
In reply to Re: Doxepin binding data? » ed_uk2010, posted by psychobot5000 on December 5, 2010, at 19:42:50
>in order to get that benefit without the other psychotropic stuff...
What is the other psychotropic stuff?
Posted by Conundrum on December 7, 2010, at 10:08:25
In reply to Re: Doxepin binding data?, posted by psychobot5000 on December 5, 2010, at 10:18:55
Nortriptyline and amitriptyline, you should be able to pull those up on PDSP. I think nortriptyline binds to the 5 HT2C receptor with a potency of 7.0.
Do you know that you respond to 5 HT2C antagonism?
> Unfortunately, it doesn't include 5ht2c binding. Anyone know which TCAs have stronger binding at 2a than 2c, or how trimipramine fairs in this regard? (PDSP doesn't come up with much for trimipramine)
Posted by Conundrum on December 7, 2010, at 10:10:04
In reply to Re: Doxepin binding data? )) Sigismund » psychobot5000, posted by sigismund on December 7, 2010, at 1:27:17
3 PM? Mirtazapine has a half life around 20-40 hours. Probably towards the shorter end if you're male. I found it increased sleep length. Just got off mirtazapine and its nice to see 9 AM again.
> >(though I'm finding that the lower end may work better)
>
> I remember not liking doxepin.
>
> I actually preferred mirtazepine (until I got up), perhaps because it deepened sleep.
> Then I had to wait until 3pm to feel that the poison had left my system.
>
> Doxepin did not seem to deepen sleep in the same way, IIRC.
Posted by ed_uk2010 on December 7, 2010, at 13:32:34
In reply to Re: Doxepin binding data? » psychobot5000, posted by sigismund on December 7, 2010, at 1:29:11
Mirtazapine does not agree with me, but it's definitely not as bad as amitriptyline. On amitriptyline, I cannot function at all. I can't even tolerate 10mg of ami. SSRIs are much more tolerable for me. They cause the usual side effects (eg. low libido, reduced emotional response) but nothing horrible. Vilazodone sounds interesting. I'd actually want to try that one when it comes out.
Posted by sigismund on December 7, 2010, at 16:04:12
In reply to Re: Doxepin binding data? » sigismund, posted by ed_uk2010 on December 7, 2010, at 13:32:34
>On amitriptyline, I cannot function at all. I can't even tolerate 10mg of ami.
I took 25mg once and once only.
Posted by psychobot5000 on December 7, 2010, at 16:10:17
In reply to Re: Doxepin binding data? » psychobot5000, posted by Conundrum on December 7, 2010, at 10:08:25
Thanks for the tip, re: ami. I do respond to 5ht2c antagonism, as far as I can tell, though in the long term, the response is counterproductive.
As for the rest, both amitryp and remeron make me a bit zombieish, unfortunately.
Best,
PB
Posted by sigismund on December 7, 2010, at 16:40:30
In reply to Re: Doxepin binding data? » Conundrum, posted by psychobot5000 on December 7, 2010, at 16:10:17
> I do respond to 5ht2c antagonism, as far as I can tell, though in the long term, the response is counterproductive.
That's the part of the agomelatine effect that has proved durable for me.
The melatonin agonism thingo has not.
Posted by Conundrum on December 7, 2010, at 22:16:51
In reply to Re: Doxepin binding data? » Conundrum, posted by psychobot5000 on December 7, 2010, at 16:10:17
Low dose prozac might help, like taking 5 mg every other day, it doesn't seem to be such a strong SSRI at that dose. I believe that at that dose it is working via 5 HT2C antagonism and 5 HT1A agonism.
> Thanks for the tip, re: ami. I do respond to 5ht2c antagonism, as far as I can tell, though in the long term, the response is counterproductive.
>
> As for the rest, both amitryp and remeron make me a bit zombieish, unfortunately.
>
> Best,
> PB
Posted by Conundrum on December 7, 2010, at 22:23:44
In reply to Re: Doxepin binding data?, posted by sigismund on December 7, 2010, at 16:40:30
> > I do respond to 5ht2c antagonism, as far as I can tell, though in the long term, the response is counterproductive.
>
> That's the part of the agomelatine effect that has proved durable for me.
>
> The melatonin agonism thingo has not.How do the effects manifest themselves?
I tried remeron but it pooped out, similar effect as low dose prozac, but very strong initially. Enough to get me transcribing music in my head at work. Haven't done that ins 8 years.
Posted by sigismund on December 8, 2010, at 6:51:48
In reply to Re: Doxepin binding data? » sigismund, posted by Conundrum on December 7, 2010, at 22:23:44
To begin with I slept in. Now I don't. It's back to square one.
But I can function better on too little sleep. It feels like some kind of stimulating effect, I guess.
Posted by Conundrum on December 8, 2010, at 10:31:37
In reply to Re: Doxepin binding data? » Conundrum, posted by sigismund on December 8, 2010, at 6:51:48
> To begin with I slept in. Now I don't. It's back to square one.
>
> But I can function better on too little sleep. It feels like some kind of stimulating effect, I guess.Its tempting to want to order it, but i'm skeptical that it wouldn't work in the long run, drugs like abilify and remeron pooped out, makes me think that drugs that work solely by antagonizing or agonizing receptors directly, cause fast upregulation or sensitization in me.
Posted by sigismund on December 8, 2010, at 12:46:55
In reply to Re: Doxepin binding data?, posted by Conundrum on December 8, 2010, at 10:31:37
> makes me think that drugs that work solely by antagonizing or agonizing receptors directly, cause fast upregulation or sensitization in me.
Do you have a plan?
Posted by sigismund on December 9, 2010, at 11:36:23
In reply to Re: Doxepin binding data?, posted by Conundrum on December 8, 2010, at 10:31:37
Here's something I hadn't seen before....
Data among the first positive evidence for the role of triple reuptake inhibitors in depression
Euthymics Bioscience, Inc. today will present Phase II clinical data demonstrating that its lead product candidate EB-1010, a next-generation antidepressant, is effective for treating major depressive disorder (MDD) based on multiple standard measures of outcome for depression. EB-1010 also improved measures of anhedonia, a hallmark symptom of MDD, which is characterized by the inability to experience pleasure. The data further demonstrate that EB-1010 is well tolerated, without the weight gain or sexual dysfunction associated with the most common pharmacological treatments for depression. The data are being presented at the 49th annual meeting of the American College of Neuropsychopharmacology (ACNP) in Miami, Florida.
Euthymics EB-1010 is a novel unbalanced triple reuptake inhibitor antidepressant intended for patients with MDD who do not respond adequately to selective serotonin reuptake inhibitors (SSRIs), a class which comprises the most common medications in the antidepressant market, which is currently valued at nearly $20 billion worldwide, according to IMS. However, a large subset of patients with major depression - about 66% - do not experience remission after an adequate initial treatment with SSRIs, according to the STAR*D study, a large seven-year study sponsored by the National Institutes of Mental Health. STAR*D also showed that outcomes improved when patients were treated with multiple medications to modulate the key monoamines associated with depression, namely, serotonin, norepinephrine and dopamine. EB-1010 replicates this triple profile in a single medication.
These data represent convincing Phase II proof-of-concept efficacy for EB-1010 in MDD. More importantly, they validate the potential of a unique unbalanced triple reuptake inhibition profile to treat a large segment of MDD patients with significant unmet medical need, said Pierre V. Trān, M.D., Euthymics Chief Medical Officer, and lead author on the presentation. These results clearly support further development of EB-1010.
As an unbalanced triple reuptake inhibitor, EB-1010 demonstrates greatest affinity for the transporters that inhibit serotonin reuptake, half as much against norepinephrine reuptake and one-eighth as much against dopamine reuptake, resulting in a ratio of 1:2:8. Balanced triples have equal affinity for the three monoamines, but have not demonstrated efficacy in depression, which makes these data even more striking.
The data presented are from a multicenter, randomized, placebo-controlled, double-blind, six-week study in patients with major depressive disorder (MDD). Sixty-three patients in the U.S. and in Eastern Europe were randomized, and 56 patients were included in the modified intent-to-treat population (MITT) at a titrated dose of 50 mg/day for two weeks and then 100 mg/day for the remaining four weeks. Efficacy results were statistically significantly superior when compared to placebo on the primary outcome measure, the Montgomery-Åsberg Depression Rating Scale (MADRS, 18.16 vs. 21.99; p=0.028). Secondary measures including the Clinical Global Impression-Improvement (CGI-I) scale, compared to placebo (p=0.03) as well as anhedonia factor scores derived from the MADRS (p=0.049), were also improved. The safety evaluation showed a benign adverse event profile with no marked difference between EB-1010 and placebo. EB-1010 did not cause a loss in sexual function over the course of the trial and the study indicated a weight-neutral profile.
Using treatment effect analysis to compare among antidepressants, EB-1010 achieved roughly double the efficacy of SSRIs with a Cohens d of -0.63 without the side effects associated with first-line treatments for depression, said Anthony A. McKinney, President and CEO of Euthymics. These data, when carefully analyzed, were so compelling they supported our ability to close a $24 million Series A financing, which we anticipate will be sufficient to fund a major Phase II/III trial to commence in spring 2011.
Euthymics plans to initiate TRIADE (Triple Reuptake Inhibitor Anti-Depressant Effects), a large multicenter Phase II/III clinical trial of EB-1010 in major depression in the first half of 2011. Maurizio Fava, M.D., Professor of Psychiatry at Harvard Medical School and Executive Vice Chair of the Department of Psychiatry at Massachusetts General Hospital will serve as principal investigator for TRIADE.
A second presentation at the ACNP meeting reviewed the preclinical pharmacology of EB-1010 including its inhibition of serotonin, norepinephrine and dopamine uptake transporters. The addition of dopamine to SSRIs has been shown to improve many symptoms of depression that are poorly treated by SSRIs alone. These poorly treated symptoms of depression include cognitive impairment, anhedonia, fatigue and sleepiness. Dopamine neurotransmission also diminishes troublesome effects of many current treatments including sexual dysfunction and weight gain. Dopamine likely plays an important role in the preservation of sexual function as well as the improvement in the ability to perceive pleasure (anhedonia).
This is the end of the thread.
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