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Re: wash-out before maoi King Vultan

Posted by zeugma on May 24, 2004, at 13:25:56

In reply to Re: wash-out before maoi, posted by King Vultan on May 24, 2004, at 8:03:25

> > >
> >
> > Trazodone, Serzone & Nortriptyline are all 5-HT2A & Alpha-1 NE blockers, I'd be interested to know which receptor blockade causes you grief. A Remeron trial could be revealing, it stands out from the other sedating AD's because it doesn't block Alpha-1 NE.
> >
> > Have you tried the other antihistamine for sleep like Phenergan & Polaramine? Phenergan might be bad, I think it would hit a bunch of receptors.
> >
> > Cheers,
> > Panda.
> >
> >
> >
> My theory is that it is these drugs' blockade of 5HT-1 receptors that is responsible. For trazodone I have a reference showing these Ki values in order of strength:
> alpha-1..... 12 +/- 0.2
> 5-HT2A..... 20 +/- 1
> 5-HT1A..... 29 +/- 1
> alpha-2..... 106 +/- 2
> Furthermore, the trazodone metabolite mCPP shows these Ki values:
> 5-HT1A..... 16 +/- 0.2
> alpha-1..... 97 +/- 3
> 5-HT2A..... 110 +/- 3
> So for the parent molecule, the 5-HT1A blockade is the 3rd most powerful--and of roughly the same order of magnitude as the alpha-1 blockade. For mCPP, the 5-HT1A blockade is by far the most powerful.
> So what does this mean? I'm not sure, but I bring it up because the 5-HT1A receptor seems like a strange one for an antidepressant to be blockading. After all, the presynaptic 5-HT1A receptor is the initial target and the postsynaptic 5-HT1A receptor is the ultimate target for SSRIs to stimulate. To me, it doesn't sound like a great idea to be blockading this receptor, but trazodone--and Serzone, which has a very similar pharmacology--obviously work as antidepressants for some people. My theory is that this weird 5-HT1A blockade business is one of the reasons these drugs are viewed by some as marginal antidepressants. I also think that someone like myself who reacts very strongly and quickly to an SSRI will have a greater chance of finding Serzone and trazodone to be disappointing.

The azapirones- buspirone and gepirone- are 5-HT 1A agonists, and they are even more marginal antidepressants than trazodone and the soon to be discontinued Serzone. The azapirones have even worse pharmacokinetics than trazodone and Serzone - i.e. shorter half lives, and some people claim that this is the reason they have exhibited so little success when treating depression- or anxiety, for that matter. We will see when gepirone is released in an ER formulation, but from what I have heard buspirone ER was not a notable success.

As for nortriptyline, nobody has ever claimed it is a marginal antidepressant. So maybe for a good proprtion of people its antiserotonergetic effects are therapeutic?

> As for nortriptyline, I don't have statistical data, but in the receptor chart in "Psychotropic Drugs", its Ki for 5-HT1 blockade, represented by ++, is higher than most of the tricyclics, and it also has only a relatively weak blockade of serotonin reuptake to counterbalance it (its most powerful effect is its blockade of NE reuptake). I found nortriptyline to have kind of a dual action, as in one way I was getting a lift, and in another I was going down in the dumps. There was enough lift, however, that there was a net antidepressant effect.
> None of this appears to apply to Remeron, which my book shows has zero effect on blockading 5-HT1A receptors. I'm more optimistic that this drug would have antidepressant effects for me, but I am not enthusiastic about trying it due to possible oversedation and weight gain problems.
> Todd

I found nortriptyline sedating enough, so I am not going near Remeron myself. The real mystery about nortriptyline is that it is the only AD with a true therapeutic window. This window cannot be based solely on its NRI effects, or adding Strattera would have resulted in loss of antidepressant effect. (?- is this reasoning off the mark? I mention it because Strattera definitely seemed to boost nortriptyline's AD effects.)

I am going to call my pdoc later and ask him to have a script called in for clomipramine. I am probably more depressed on 50 mg nortriptyline than I was on 75 mg, and sleeping worse, so i want to try the experiment of adding clomipramine and seeing if I can get a stronger AD effect from clomipramine alone than I did from nortriptyline. Then I would like to eliminate the Strattera and try a stimulant for my ADD instead.

What does your book tell you about the receptor blocking affinities of clomipramine? Probably both 5HT-1A and 5HT 2A blockade is therapeutic for me. The great experiment will be to see what 5HT reuptake inhibition does for me, since I have never taken one long enough to determine the nature of its effects. My hope is that the other actions of clomipramine will make the SRI effects tolerable.




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