![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 8 to 32 of 32. Go back in thread:
Posted by Elizabeth on October 16, 2001, at 18:15:04
In reply to Re: California Rocket Fuel+++, posted by SLS on October 16, 2001, at 16:33:06
> Perhaps you can add the drugs in the same order stepwise while continuing desipramine, perhaps leaving it in place as a substitute for bupropion to start with.
That's a thought, although Wellbutrin SR would probably be more tolerable. I would taper off the DMI as I started the new stuff.
> I don’t know if one can think of Cylert as being a substitute for, or analogous to, Provigil. I don’t think Provigil acts directly upon dopaminergic neurons.
I think it's a DA reuptake inhibitor (a more potent one than has been implied, that is). Don't tell the FDA. :-) And I don't think it's known just what Cylert does.
-elizabeth
Posted by SLS on October 16, 2001, at 19:14:51
In reply to Re: California Rocket Fuel+++ » SLS, posted by Elizabeth on October 16, 2001, at 18:15:04
> > Perhaps you can add the drugs in the same order stepwise while continuing desipramine, perhaps leaving it in place as a substitute for bupropion to start with.
>
> That's a thought, although Wellbutrin SR would probably be more tolerable. I would taper off the DMI as I started the new stuff.
>
> > I don’t know if one can think of Cylert as being a substitute for, or analogous to, Provigil. I don’t think Provigil acts directly upon dopaminergic neurons.
> I think it's a DA reuptake inhibitor (a more potent one than has been implied, that is).No. I'm pretty sure modafinil doesn't inhibit at all the reuptake of dopamine at therapeutic dosages, and binds with low affinity to the DA transporter.
> And I don't think it's known just what Cylert does.
In the days before the flood, pemoline was considered to promote the passive release of dopamine presynaptically. It did not promote vesicular release.
I don't know if it is relevant, but the majority of patients who responded in the small open-label study of modafinil-augmentation often cited were taking bupropion. I think this was more the result of patient selection than rate of response.
- ScottClin Psychiatry 2000 May;61(5):378-81 Related Articles, Books
Modafinil augmentation of antidepressant treatment in depression.Menza MA, Kaufman KR, Castellanos A.
Posted by JohnX on October 16, 2001, at 23:25:02
In reply to California Rocket Fuel+++, posted by Elizabeth on October 15, 2001, at 10:31:03
> Hi everyone.
>
> A friend of mine who has had some troubles has recently embarked on a trial of Klonopin 4mg + Remeron 60mg + Effexor XR 400mg + Wellbutrin SR 300mg + Provigil 400mg. (He was already taking the Klonopin, and he added the others in a stepwise fashion in the order in which I listed them.) It may seem like overkill, but I've been amazed at the change in him -- to the point where I'm considering taking the risk of trying something similar myself (which would involve decreasing or eliminating some of my current cocktail). (I would probably use Cylert instead of Provigil (price concerns, plus I took Cylert before with some success), Trileptal or some other AED instead of Klonopin, and Xanax as-needed for panic attacks.)
>
> Some things make me a little bit pessimistic about this mix for me:
>
> * My friend responded to Remeron by itself (he gave it up because of weight gain), while I did not. OTOH, I had at least some response to Effexor XR, and I don't think that he was helped by Effexor alone.
>
> * I had a major serious reaction (the so-called "serotonin syndrome") that was at least in part due to Effexor XR (there were probably other contributing factors since I'd been taking it for several weeks, although I can never be sure). I've heard that Remeron (due to it's 5-HT antagonist properties) can prevent such a reaction, but I'm not sure whether I should believe this claim. I know Remeron can block some of the side effects of SSRIs and Effexor, but I'm not sure if it would prevent the serotonin syndrome. I might try it using desipramine instead of Effexor, at least to start out. Of course, then I have to worry about pharmacokinetic problems.
>
> * Despite the side effects, the buprenorphine-desipramine combination is doing so well for me that I hesitate to jeopardize my current state of full remission. My hope would be that the CRF+++ would help enough that I could take buprenorphine intermittently, or maybe even discontinue it altogether.
>
> So, does anybody have any ideas or thoughts or whatever? I'm facing a tough choice, here. In partiucular: Dr. Bob, if you have any thoughts on this I'd really like to hear them. (This goes for any other MDs or DOs who might be lurking out there.)
>
> -elizabethHow do you think you would do with all the side
effects hittin you at once? Better add the meds
one by one, as suggested. I hope you
have some experience with the other meds so you
know what to expect. I wish you the
best. After all my trials I am sticking to
the motto "If it aint broken, don't fix it".Lamictal is my main stay to keep me from major
depression, and I toy with adding things carefully
so as not to completely disrupt my life that I
am trying to repiece.Anyways,I was bored of my residual anhedonia and I took a bunch of meds that did nothing (without
side effects either), and combined them into
a cocktail (I called in Texas Rocket Fuel, but
maybe Texas Death Sentence would be better).
The combo was different but based on a theory
to perpetually stimulate norepinephrine
neurons in one part of the brain (LC) which would in turn stimulate serotonin neurons in another
(raphe projections), which in turn would shoot dopamine from the VTA up into the (pre)frontal cortex. A lot of the meds indicated they
already did this, but I had a particular reasoning
behind my cocktail, which truly knocked the dysthymia out of me without poop out or exacerbation of facial pain that a lot of meds
aggravate. I did have a terrible side effect of giving me a racing heart which inderal stopped if
I ate the wrong foodshere it was:
-Remeron 45mg
-Reboxetine 4 mg
-Manerix 300 mg
-Selegeline ~60 mg
-Pindolol ~5 mg
-Lamictal 150 mg
-Klonopin 4 mgThats 7 meds at once. My own record. And complete
stupidity. 8 if you count the inderal I took
to keep my heart from exploding! I tried to
turn the knobs to see if I could subtract things
and get the same effect, but I ran out of the
meds. I had dreams where my liver had a conversation with me asking what the *ell I was
doing. ;)Now I just take Lamictal, Zyprexa, & Klonopin. I recently dropped a Remeron trial
after adding Zyprexa.PS. Less is more. ;) Please don't forget
how you felt before you came up with your
current cocktail.Good Luck,
John
Posted by Ant-Rock on October 17, 2001, at 20:18:29
In reply to Re: California Rocket Fuel+++ » Elizabeth, posted by JohnX on October 16, 2001, at 23:25:02
> > Hi everyone.
> >
> > A friend of mine who has had some troubles has recently embarked on a trial of Klonopin 4mg + Remeron 60mg + Effexor XR 400mg + Wellbutrin SR 300mg + Provigil 400mg. (He was already taking the Klonopin, and he added the others in a stepwise fashion in the order in which I listed them.) It may seem like overkill, but I've been amazed at the change in him -- to the point where I'm considering taking the risk of trying something similar myself (which would involve decreasing or eliminating some of my current cocktail). (I would probably use Cylert instead of Provigil (price concerns, plus I took Cylert before with some success), Trileptal or some other AED instead of Klonopin, and Xanax as-needed for panic attacks.)
> >
> > Some things make me a little bit pessimistic about this mix for me:
> >
> > * My friend responded to Remeron by itself (he gave it up because of weight gain), while I did not. OTOH, I had at least some response to Effexor XR, and I don't think that he was helped by Effexor alone.
> >
> > * I had a major serious reaction (the so-called "serotonin syndrome") that was at least in part due to Effexor XR (there were probably other contributing factors since I'd been taking it for several weeks, although I can never be sure). I've heard that Remeron (due to it's 5-HT antagonist properties) can prevent such a reaction, but I'm not sure whether I should believe this claim. I know Remeron can block some of the side effects of SSRIs and Effexor, but I'm not sure if it would prevent the serotonin syndrome. I might try it using desipramine instead of Effexor, at least to start out. Of course, then I have to worry about pharmacokinetic problems.
> >
> > * Despite the side effects, the buprenorphine-desipramine combination is doing so well for me that I hesitate to jeopardize my current state of full remission. My hope would be that the CRF+++ would help enough that I could take buprenorphine intermittently, or maybe even discontinue it altogether.
> >
> > So, does anybody have any ideas or thoughts or whatever? I'm facing a tough choice, here. In partiucular: Dr. Bob, if you have any thoughts on this I'd really like to hear them. (This goes for any other MDs or DOs who might be lurking out there.)
> >
> > -elizabeth
>
> How do you think you would do with all the side
> effects hittin you at once? Better add the meds
> one by one, as suggested. I hope you
> have some experience with the other meds so you
> know what to expect. I wish you the
> best. After all my trials I am sticking to
> the motto "If it aint broken, don't fix it".
>
> Lamictal is my main stay to keep me from major
> depression, and I toy with adding things carefully
> so as not to completely disrupt my life that I
> am trying to repiece.
>
> Anyways,I was bored of my residual anhedonia and I took a bunch of meds that did nothing (without
> side effects either), and combined them into
> a cocktail (I called in Texas Rocket Fuel, but
> maybe Texas Death Sentence would be better).
> The combo was different but based on a theory
> to perpetually stimulate norepinephrine
> neurons in one part of the brain (LC) which would in turn stimulate serotonin neurons in another
> (raphe projections), which in turn would shoot dopamine from the VTA up into the (pre)frontal cortex. A lot of the meds indicated they
> already did this, but I had a particular reasoning
> behind my cocktail, which truly knocked the dysthymia out of me without poop out or exacerbation of facial pain that a lot of meds
> aggravate. I did have a terrible side effect of giving me a racing heart which inderal stopped if
> I ate the wrong foods
>
> here it was:
>
> -Remeron 45mg
> -Reboxetine 4 mg
> -Manerix 300 mg
> -Selegeline ~60 mg
> -Pindolol ~5 mg
> -Lamictal 150 mg
> -Klonopin 4 mg
>
> Thats 7 meds at once. My own record. And complete
> stupidity. 8 if you count the inderal I took
> to keep my heart from exploding! I tried to
> turn the knobs to see if I could subtract things
> and get the same effect, but I ran out of the
> meds. I had dreams where my liver had a conversation with me asking what the *ell I was
> doing. ;)
>
> Now I just take Lamictal, Zyprexa, & Klonopin. I recently dropped a Remeron trial
> after adding Zyprexa.
>
> PS. Less is more. ;) Please don't forget
> how you felt before you came up with your
> current cocktail.
>
> Good Luck,
> JohnHi John,
I'm a little confused. You stated the 7 med combo worked well for your anhedonia. But you no longer use this combo.Does this mean your current combo of 3 meds works just as well or better?
Also, does klonopin help with anhedonia/depression? I wasn't aware of this.
Anhedonia is a big problem for me, that's why I'm asking.
One more thing, the best anti-depressant/anhedonia effect I ever received was from Mirapex. I am considering going back on this med shortly, seeing that the 70mg of parnate I take doesn't touch anhedonia, and possibly makes it worse over time.
Thanks John for any info you could provide.
Anthony
Posted by Elizabeth on October 19, 2001, at 12:28:24
In reply to Re: California Rocket Fuel+++ » Elizabeth, posted by SLS on October 16, 2001, at 19:14:51
> No. I'm pretty sure modafinil doesn't inhibit at all the reuptake of dopamine at therapeutic dosages, and binds with low affinity to the DA transporter.
I'll look it up at some point. I don't have access to my books right now.
> In the days before the flood, pemoline was considered to promote the passive release of dopamine presynaptically. It did not promote vesicular release.
Well, Abbott, at any rate, denies knowledge of what it does. :-)
> I don't know if it is relevant, but the majority of patients who responded in the small open-label study of modafinil-augmentation often cited were taking bupropion.
That's interesting, since bupropion is one of the ingredients in "CRF+++."
> I think this was more the result of patient selection than rate of response.
Maybe.
-elizabeth
Posted by Elizabeth on October 19, 2001, at 12:33:06
In reply to Re: California Rocket Fuel+++ » Elizabeth, posted by JohnX on October 16, 2001, at 23:25:02
> How do you think you would do with all the side
> effects hittin you at once?I tried all of them by themselves and they didn't have any major side effects. I think I'll be fine (if I end up trying this "med soup").
> Better add the meds one by one, as suggested.
Of course. That's always how I do polypharmacy,
> After all my trials I am sticking to
> the motto "If it aint broken, don't fix it".It's just a little bit broken. You know?
> -Remeron 45mg
> -Reboxetine 4 mg
> -Manerix 300 mg
> -Selegeline ~60 mg
> -Pindolol ~5 mg
> -Lamictal 150 mg
> -Klonopin 4 mgI'm not into the idea of mixing high-dose selegiline (which really didn't agree with me, anyway) with all those other ADs.
> Thats 7 meds at once. My own record.
Ha, I have you beat. :-)
-elizabeth
Posted by Andy123 on October 19, 2001, at 18:19:05
In reply to Re: California Rocket Fuel+++ ?Peter S., posted by Elizabeth on October 16, 2001, at 18:09:45
Why don't you try milk of magnesia for the bup/des side effect.
> > If I might ask: what's your current regimen? What are the side effects that are so disturbing? Are they primarily from the bup?
>
> Yes. I'm taking:
>
> buprenorphine 0.3 mg (1 mL) t.i.d.
> desipramine 200 mg b.i.d.
> trileptal 150 mg b.i.d.
> clonazepam 1-2 mg p.r.n.
>
> plus some propranolol, bethanechol, Metamucil, and several antihistamines to counteract side effects.
>
> The side effects are mostly caused by bupe, although some of them are probably exacerbated by the desipramine. Constipation is the most difficult one: I have to take Metamucil several times a day (kind of a hassle because
> and even then it's still pretty bad sometimes. There's also some really bad dry mouth. Antihistamines don't seem to work very well for the pruritis ("the itchies"). I think that something (not sure which) is causing some sexual problems, and I sometimes get carbohydrate cravings which might be from taking large doses of antihistamines.
>
> It's just so much stuff to manage, you know?
>
> -elizabeth
Posted by JohnX on October 21, 2001, at 14:02:35
In reply to Re: California Rocket Fuel+++ » JohnX, posted by Elizabeth on October 19, 2001, at 12:33:06
Good luck. You answered my concerns
tit-for-tat. and you seem to be well
aware of interactions.Keep us posted on your "cocktail".
I suggest comming up with a more snazy
name, it's your invention!-John
> > How do you think you would do with all the side
> > effects hittin you at once?
>
> I tried all of them by themselves and they didn't have any major side effects. I think I'll be fine (if I end up trying this "med soup").
>
> > Better add the meds one by one, as suggested.
>
> Of course. That's always how I do polypharmacy,
>
> > After all my trials I am sticking to
> > the motto "If it aint broken, don't fix it".
>
> It's just a little bit broken. You know?
>
> > -Remeron 45mg
> > -Reboxetine 4 mg
> > -Manerix 300 mg
> > -Selegeline ~60 mg
> > -Pindolol ~5 mg
> > -Lamictal 150 mg
> > -Klonopin 4 mg
>
> I'm not into the idea of mixing high-dose selegiline (which really didn't agree with me, anyway) with all those other ADs.
>
> > Thats 7 meds at once. My own record.
>
> Ha, I have you beat. :-)
>
> -elizabeth
Posted by Elizabeth on October 22, 2001, at 10:33:12
In reply to Re: California Rocket Fuel+++ » Elizabeth, posted by SLS on October 16, 2001, at 19:14:51
> > I think it's a DA reuptake inhibitor (a more potent one than has been implied, that is).
>
> No. I'm pretty sure modafinil doesn't inhibit at all the reuptake of dopamine at therapeutic dosages, and binds with low affinity to the DA transporter.Do you know what the K_d is, BTW?
-e
Posted by Elizabeth on October 22, 2001, at 10:36:12
In reply to Re: California Rocket Fuel+++, posted by Andy123 on October 19, 2001, at 18:19:05
> Why don't you try milk of magnesia for the bup/des side effect.
Howdy stranger. :)
I went out and got some magnesium citrate, will see what that does.
I think that the buprenorphine is the cause of most or all of that problem, BTW. Desipramine doesn't seem to have caused any side fx at all, even when my serum level was 600+ ng/mL.
-e
Posted by Elizabeth on October 22, 2001, at 10:39:34
In reply to Re: California Rocket Fuel+++ » Elizabeth, posted by JohnX on October 21, 2001, at 14:02:35
> Good luck. You answered my concerns
> tit-for-tat. and you seem to be well
> aware of interactions.Of course!
> Keep us posted on your "cocktail".
> I suggest comming up with a more snazy
> name, it's your invention!CRF is a popular name for the Remeron-Effexor cocktail; I think Stahl is credited with coining the expression. I haven't come up with an exact cocktail of my own, so for now, it's just "California Rocket Fuel +++." :-)
-elizabeth
Posted by Elizabeth on October 26, 2001, at 16:37:59
In reply to Re: California Rocket Fuel+++ » Elizabeth, posted by SLS on October 16, 2001, at 19:14:51
Since this discussion ("California Rocket Fuel +++") didn't carry over and I'm still hoping somebody has relevant experience, I'm posting again...
I'm interested in drug combinations involving Remeron and Effexor and possibly other antidepressants, stimulants, etc. Anybody had success with such a combination? I'm particularly (though not exclusively) interested in whether this kind of mix could work when the components by themselves have failed or proven intolerable.
Also, I had a question (in response to something that SLS said) that went unanswered, and I haven't been able to dig up an answer to it either so I'm hoping somebody might know or be able to find out:
SLS said:
> I'm pretty sure modafinil doesn't inhibit at all the reuptake of dopamine at therapeutic dosages, and binds with low affinity to the DA transporter.I wanted to know if anybody knows what the K_d is. That would be useful to know.
-elizabeth
Posted by Elizabeth on October 26, 2001, at 20:03:27
In reply to Re: CA rocket fuel; modafinil pharmacology » Elizabeth, posted by Westsidaz on October 26, 2001, at 18:45:13
> I know for sure that Provigil has no appreciable action on dopamine. I even tried it as an adjunct to MAOIs and didn't benefit from it. It didn't even wake me up on Parnate.
Thanks for your input, but that wasn't what I asked. (In any case, subjective experience proves nothing about the pharmacodynamics of a drug.)
Posted by JohnX2 on October 27, 2001, at 11:29:18
In reply to Re: California Rocket Fuel+++ » JohnX, posted by Elizabeth on October 22, 2001, at 10:39:34
How's that cocktail going?
It needs an official name!!!!Give me something to giggle about ;)
regards,
Jams
> > Good luck. You answered my concerns
> > tit-for-tat. and you seem to be well
> > aware of interactions.
>
> Of course!
>
> > Keep us posted on your "cocktail".
> > I suggest comming up with a more snazy
> > name, it's your invention!
>
> CRF is a popular name for the Remeron-Effexor cocktail; I think Stahl is credited with coining the expression. I haven't come up with an exact cocktail of my own, so for now, it's just "California Rocket Fuel +++." :-)
>
> -elizabeth
Posted by JohnX2 on October 28, 2001, at 2:09:17
In reply to CA rocket fuel; modafinil pharmacology, posted by Elizabeth on October 26, 2001, at 16:37:59
Elizabeth,How does one use Kd information? Also, how do the
people who compute this do it for medications that
are "pro-drugs"? For example Bupropion Kd info
says that the med should do squat, but the
researchers have determined that the metabolite
hydroxybupropion does most of the work.
Also, how often is Kd collected from primates instead
of rats?-john
> Since this discussion ("California Rocket Fuel +++") didn't carry over and I'm still hoping somebody has relevant experience, I'm posting again...
>
> I'm interested in drug combinations involving Remeron and Effexor and possibly other antidepressants, stimulants, etc. Anybody had success with such a combination? I'm particularly (though not exclusively) interested in whether this kind of mix could work when the components by themselves have failed or proven intolerable.
>
> Also, I had a question (in response to something that SLS said) that went unanswered, and I haven't been able to dig up an answer to it either so I'm hoping somebody might know or be able to find out:
>
> SLS said:
> > I'm pretty sure modafinil doesn't inhibit at all the reuptake of dopamine at therapeutic dosages, and binds with low affinity to the DA transporter.
>
> I wanted to know if anybody knows what the K_d is. That would be useful to know.
>
> -elizabeth
Posted by Elizabeth on October 28, 2001, at 10:36:21
In reply to Re: CA rocket fuel; modafinil pharmacology » Elizabeth, posted by JohnX2 on October 28, 2001, at 2:09:17
> How does one use Kd information?
Do you know any biochemistry? Kd (the d is supposed to be a subscript, BTW) is the dissociation constant (in this case, for modafinil at the dopamine transporter).
> For example Bupropion Kd info
> says that the med should do squat, but the
> researchers have determined that the metabolite
> hydroxybupropion does most of the work.Yes, hydroxybupropion does appear to be responsible for much of the therapeutic efficacy of Wellbutrin, but AFAIK, the mechanism of action of the metabolite is not understood either. Of course the pharmacology of the hydroxy metabolite will need to be determined if we are to find out what makes Wellbutrin an effective antidepressant. We also need to know the degree to which bupropion is metabolized into hydroxybupropion (this has probably been determined by now), and various other things -- this stuff is pretty complicated.
I don't have answers for your other questions, I'm afraid. Perhaps someone else could help us out here. (Also, I haven't started any CRF-like cocktail -- I'm still taking desipramine + buprenorphine + Trileptal. I promise to come up with a silly name for whatever I do end up taking, though. :-) )
-elizabeth
Posted by Rick on October 29, 2001, at 1:36:25
In reply to Re: California Rocket Fuel+++ » Elizabeth, posted by SLS on October 16, 2001, at 19:14:51
>I don't know if it is relevant, but the majority of patients who responded in the small open-label study of modafinil-augmentation often cited were taking bupropion. I think this was more the result of patient selection than rate of response.
- Scott>Clin Psychiatry 2000 May;61(5):378-81 Related Articles, Books
>Modafinil augmentation of antidepressant treatment in depression.>Menza MA, Kaufman KR, Castellanos A.
This may be even *less* relevant, but for the record there were 7 patients in the Provigil (modafinil) augmentation study often cited. Here's the lineup:
#1 Celexa (citalopram) and Wellbutrin (bupropion)
#2 Wellbutrin and Deseryl (trazodone)
#3 Celexa
#4 Celexa
#5 Wellbutrin, Depakote (divalproex), and Lamictal (limotrigine)
#6 Serzone (nefazodone) and Paxil (paroxetine)
#7 Effexor (venlafaxine)The attached link gives more patient details including age, diagnosis, previous meds, time to initial effect, and brief analysis.
Rick
http://alertpubs.com/august2000psych.htm#Stimulant Augmentation in Depression
Posted by SLS on October 29, 2001, at 8:58:42
In reply to CA rocket fuel; modafinil pharmacology, posted by Elizabeth on October 26, 2001, at 16:37:59
> Since this discussion ("California Rocket Fuel +++") didn't carry over and I'm still hoping somebody has relevant experience, I'm posting again...
>
> I'm interested in drug combinations involving Remeron and Effexor and possibly other antidepressants, stimulants, etc. Anybody had success with such a combination? I'm particularly (though not exclusively) interested in whether this kind of mix could work when the components by themselves have failed or proven intolerable.
>
> Also, I had a question (in response to something that SLS said) that went unanswered, and I haven't been able to dig up an answer to it either so I'm hoping somebody might know or be able to find out:
>
> SLS said:
> > I'm pretty sure modafinil doesn't inhibit at all the reuptake of dopamine at therapeutic dosages, and binds with low affinity to the DA transporter.
>
> I wanted to know if anybody knows what the K_d is. That would be useful to know.
>
> -elizabeth
I've been feeling less than spectacular, so please forgive my dereliction. I've explored modafinil well enough to feel confident that it is not at this time considered to be active directly upon dopaminergic neurons. I'm sure you can find all of the material necessary to assess this for yourself. Probably the best way to go about things is to call Cephalon directly and speak to one of their pharmacologists. Perhaps they have reconsidered their previous conclusions.You might check this out:
http://www.provigil.com/physician/materials/default.asp
It probably doesn't hurt too much to occasionally treat the brain as a black-box. Provigil seems pretty safe.
- Scott
Posted by Elizabeth on October 29, 2001, at 10:44:20
In reply to Re: CA rocket fuel; modafinil pharmacology » Elizabeth, posted by SLS on October 29, 2001, at 8:58:42
> I've been feeling less than spectacular, so please forgive my dereliction.
Sorry to hear it. I just thought that maybe you'd missed my question,
> I've explored modafinil well enough to feel confident that it is not at this time considered to be active directly upon dopaminergic neurons.
If it were, do you think that Cephalon would want to know? I don't. It's C-IV, they want it to stay C-IV.
The only relevant data I could find in the PI:
"In vitro, modafinil binds to the dopamine reuptake site and causes an increase in extracellular dopamine, but no increase in dopamine release." [no information about in vivo activity is provided]
"In addition to its wakefulness-promoting effects and increased locomotor activity in animals, in humans, PROVIGIL produces psychoactive and euphoric effects, alterations in mood, perception, thinking, and feelings typical of other CNS stimulants. Modafinil is reinforcing, as evidenced by its self-administration in monkeys previously trained to self-administer cocaine; modafinil was also partially discriminated as stimulant-like."
The PI lists lots of things that modafinil *doesn't* do, but doesn't include any hypothesis as to what action might be responsible for its effects (in particular, the effects described in the second quotation above). Maybe the dopaminergic-like effects are the result of some action other than dopamine transporter blockade -- but what that mechanism might be is unclear. I want to find out the Kd with respect to the DA transporter because that would allow me to decide for myself whether DA reuptake inhibition is significant at clinically-used doses.
> I'm sure you can find all of the material necessary to assess this for yourself.
As I said, I wasn't able to find out the Kd for modafinil (despite my not-so-vast resources) and I was wondering if you knew it or any other relevant information.
> It probably doesn't hurt too much to occasionally treat the brain as a black-box. Provigil seems pretty safe.
I'm certainly not disputing that. I think it's a fine drug, and probably more effective for ADD, depression, chronic fatigue, etc., than it is for narcolepsy. (In fact, I don't understand why it's marketed for narcolepsy at all -- except, of course, for political reasons.)
-elizabeth
Posted by houstongirl on October 29, 2001, at 13:42:13
In reply to Re: Cal Rocket Fuel - Clarification on modaf study » SLS, posted by Rick on October 29, 2001, at 1:36:25
I thought there was a known metabolic interaction between citalopram and modafinil?
> >I don't know if it is relevant, but the majority of patients who responded in the small open-label study of modafinil-augmentation often cited were taking bupropion. I think this was more the result of patient selection than rate of response.
>
>
> - Scott
>
> >Clin Psychiatry 2000 May;61(5):378-81 Related Articles, Books
>
>
> >Modafinil augmentation of antidepressant treatment in depression.
>
> >Menza MA, Kaufman KR, Castellanos A.
>
>
> This may be even *less* relevant, but for the record there were 7 patients in the Provigil (modafinil) augmentation study often cited. Here's the lineup:
> #1 Celexa (citalopram) and Wellbutrin (bupropion)
> #2 Wellbutrin and Deseryl (trazodone)
> #3 Celexa
> #4 Celexa
> #5 Wellbutrin, Depakote (divalproex), and Lamictal (limotrigine)
> #6 Serzone (nefazodone) and Paxil (paroxetine)
> #7 Effexor (venlafaxine)
>
> The attached link gives more patient details including age, diagnosis, previous meds, time to initial effect, and brief analysis.
>
> Rick
>
> http://alertpubs.com/august2000psych.htm#Stimulant Augmentation in Depression
Posted by SLS on October 29, 2001, at 17:28:48
In reply to Re: modafinil pharmacology » SLS, posted by Elizabeth on October 29, 2001, at 10:44:20
> As I said, I wasn't able to find out the Kd for modafinil (despite my not-so-vast resources) and I was wondering if you knew it or any other relevant information.
Hi Elizabeth.Since you really, *really* want some info, I fired-up a few neurons and put some things together for you. It's the least I could do for someone so genuinely helpful. I hope it helps.
The statements appearing in the package insert you cited certainly are consistent with a dopaminomimetic agent. However, based upon my reading, I would guess it possible that the euphoriant and reinforcing properties of modafinil are the result of its ability to promote glutamatergic neurotransmission along pathways afferent to the nucleus accumbens.
From what little I've read of modafinil, I would say that:
1. The wakefullness-promoting effects are produced via increased release of glutamate in the hypothalamus.
2. Euphoriant effects and increased vigilence are produced via increased release of glutamate in the thalamus and hippocampus.
3. For both phenomena, it might be that the balance of glutamatergic to GABAergic activity in these areas is pushed towards the former and causes a sort of disinhibition upon reticular and limbic pathways respectively.
Please see:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9759978&dopt=Abstract
That's about the best I can do for you at this point.
This might be of some help:
http://www.nevapress.com/cnsdr/full/5/3/193.pdf
Perhaps adrafinil possesses DAergic properties that modafinil does not. From the personal experiences described by people on Psycho-Babble, it would seem that adrafinil is different enough from its metabolite (modafinil) to be considered separately. I don't believe either one acts as a NE alpha-1 agonist as was once thought.
I'd be curious to see what conclusions you come up with regarding modafinil. I would be happy to discover it to be a DA reuptake inhibitor. Some of the studies showing it to spare DA terminals of the toxic effects of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) might suggest a direct effect. I don't know. However, the authors of the following study state that this is not the result of DA reuptake inhibition.
Maybe when I get well, I'll have the brain power to figure some of this stuff out. I guess I'll just keep praying. In the meantime, feel free to pester your S.O. to lend us some of his.
Also...I don't have ready access to medical journals, but perhaps you'll find the following citation useful. No abstract was available on Medline. Even so, this would represent but one study. It would be nice to see a bunch of corraborating investigations assaying DAT affinity.
---------------------------------------------------
Sleep 1994 Aug;17(5):436-7 Related Articles, Books, LinkOut
Modafinil binds to the dopamine uptake carrier site with low affinity.Mignot E, Nishino S, Guilleminault C, Dement WC.
Stanford Sleep Disorders Center, Palo Alto, California.
---------------------------------------------------
Take care.- Scott
Posted by Rick on October 29, 2001, at 22:50:10
In reply to Re: Cal Rocket Fuel - Clarification on modaf study, posted by houstongirl on October 29, 2001, at 13:42:13
Yeah, I noticed that too but didn't want to open a can of worms. I can easily think of a dozen possible explanations, starting with methodological isssues (e.g., small sample size for the 7-person study; lack of AD dosage info for both that study AND the study citing the frequent metabolic interaction between Celexa (citalopram) and Provigil; the latter study's stronger focus on reduction of fatigue side effects (vs. enhancing AD response), etc. And there's always YMMV -- plenty of people do well on a med that has been shown to have a *statistically* insignificant effect for their disorder. I wonder when, and if, the study mentioning the metabolic reaction will appear in Medline, given that it was presented to the APA convention in May?I *have* done a little seraching through the newsgroups and do sense lower success combining Provigil (modafinil) with Celexa than with other AD's. One person reported better depression response from Provigil alone than from a Provigil/Celexa combo! And for the record, there were plenty of people taking other AD's who were by no means enamored of Provigil as an augmentor. ( But you certainly can't count me among the disenchanted group with my 2-years-and-stronger-than-ever Serzone/Klonopin/Provigil Social Phobia cocktail!)
Perhaps a telling point from the 7-person study is that the two patients taking Provigil with Celexa alone (a third took it in tandem with activating Wellbutrin) had the slowest response to their combo with Provigil (although still relatively quick). Also note that these same patients had the lowest baseline depression severity, so maybe they didn’t need as big a punch from the Provigil.
Again, I can think of lots more possibilities, such as inter-individual variation in enzyme production, but I’ll stop here.
Rick
> I thought there was a known metabolic interaction between citalopram and modafinil?
>
> > >I don't know if it is relevant, but the majority of patients who responded in the small open-label study of modafinil-augmentation often cited were taking bupropion. I think this was more the result of patient selection than rate of response.
> >
> >
> > - Scott
> >
> > >Clin Psychiatry 2000 May;61(5):378-81 Related Articles, Books
> >
> >
> > >Modafinil augmentation of antidepressant treatment in depression.
> >
> > >Menza MA, Kaufman KR, Castellanos A.
> >
> >
> > This may be even *less* relevant, but for the record there were 7 patients in the Provigil (modafinil) augmentation study often cited. Here's the lineup:
> > #1 Celexa (citalopram) and Wellbutrin (bupropion)
> > #2 Wellbutrin and Deseryl (trazodone)
> > #3 Celexa
> > #4 Celexa
> > #5 Wellbutrin, Depakote (divalproex), and Lamictal (limotrigine)
> > #6 Serzone (nefazodone) and Paxil (paroxetine)
> > #7 Effexor (venlafaxine)
> >
> > The attached link gives more patient details including age, diagnosis, previous meds, time to initial effect, and brief analysis.
> >
> > Rick
> >
> > http://alertpubs.com/august2000psych.htm#Stimulant Augmentation in Depression
> I thought there was a known metabolic interaction between citalopram and modafinil?
>
> > >I don't know if it is relevant, but the majority of patients who responded in the small open-label study of modafinil-augmentation often cited were taking bupropion. I think this was more the result of patient selection than rate of response.
> >
> >
> > - Scott
> >
> > >Clin Psychiatry 2000 May;61(5):378-81 Related Articles, Books
> >
> >
> > >Modafinil augmentation of antidepressant treatment in depression.
> >
> > >Menza MA, Kaufman KR, Castellanos A.
> >
> >
> > This may be even *less* relevant, but for the record there were 7 patients in the Provigil (modafinil) augmentation study often cited. Here's the lineup:
> > #1 Celexa (citalopram) and Wellbutrin (bupropion)
> > #2 Wellbutrin and Deseryl (trazodone)
> > #3 Celexa
> > #4 Celexa
> > #5 Wellbutrin, Depakote (divalproex), and Lamictal (limotrigine)
> > #6 Serzone (nefazodone) and Paxil (paroxetine)
> > #7 Effexor (venlafaxine)
> >
> > The attached link gives more patient details including age, diagnosis, previous meds, time to initial effect, and brief analysis.
> >
> > Rick
> >
> > http://alertpubs.com/august2000psych.htm#Stimulant Augmentation in Depression
Posted by Rick on October 29, 2001, at 23:43:31
In reply to Re: Cal Rocket Fuel - Clarification on modaf study » houstongirl, posted by Rick on October 29, 2001, at 22:50:10
Cristy -
Just recalled from another thread that you're taking a *very* high dose of Celexa (100mg.)
Given that the most likely interaction would cause Provigil to INCREASE blood levels of Celexa (through inhibition of the CYP 2C19 enzyme that Celexa needs for elimination), I'm not surprised you're having trouble keeping your eyes open!Sounds like you've been through about all the SSRI's, plus Tricyclics and Wellbutrin. Have you tried Serzone or Remeron? These can be even more sedating than SSRI's (Remeron even more so than Serzone), but Provigil would likely work a lot better with these than with Celexa, and the their unique mechanisms often help folks who were unresponsive to other AD's. I like Serzone -- as long as I can counteract the sedation effects (which not EVERYONE has) with Provigil -- because it maintains sexual function without added anxiety, among other benefits. As you well know everyone reacts differently, but these might be worth considering, or maybe an MAOI as I believe kregpark suggested (these often work wonders for nonresponders to other AD's, although there are some food restrictions).
Sorry to hear you lost your job. Hang in there, you'll get where you need to be.
Rick
> Yeah, I noticed that too but didn't want to open a can of worms. I can easily think of a dozen possible explanations, starting with methodological isssues (e.g., small sample size for the 7-person study; lack of AD dosage info for both that study AND the study citing the frequent metabolic interaction between Celexa (citalopram) and Provigil; the latter study's stronger focus on reduction of fatigue side effects (vs. enhancing AD response), etc. And there's always YMMV -- plenty of people do well on a med that has been shown to have a *statistically* insignificant effect for their disorder. I wonder when, and if, the study mentioning the metabolic reaction will appear in Medline, given that it was presented to the APA convention in May?
>
> I *have* done a little seraching through the newsgroups and do sense lower success combining Provigil (modafinil) with Celexa than with other AD's. One person reported better depression response from Provigil alone than from a Provigil/Celexa combo! And for the record, there were plenty of people taking other AD's who were by no means enamored of Provigil as an augmentor. ( But you certainly can't count me among the disenchanted group with my 2-years-and-stronger-than-ever Serzone/Klonopin/Provigil Social Phobia cocktail!)
>
> Perhaps a telling point from the 7-person study is that the two patients taking Provigil with Celexa alone (a third took it in tandem with activating Wellbutrin) had the slowest response to their combo with Provigil (although still relatively quick). Also note that these same patients had the lowest baseline depression severity, so maybe they didn’t need as big a punch from the Provigil.
>
> Again, I can think of lots more possibilities, such as inter-individual variation in enzyme production, but I’ll stop here.
>
> Rick
>
> > I thought there was a known metabolic interaction between citalopram and modafinil?
> >
> > > >I don't know if it is relevant, but the majority of patients who responded in the small open-label study of modafinil-augmentation often cited were taking bupropion. I think this was more the result of patient selection than rate of response.
> > >
> > >
> > > - Scott
> > >
> > > >Clin Psychiatry 2000 May;61(5):378-81 Related Articles, Books
> > >
> > >
> > > >Modafinil augmentation of antidepressant treatment in depression.
> > >
> > > >Menza MA, Kaufman KR, Castellanos A.
> > >
> > >
> > > This may be even *less* relevant, but for the record there were 7 patients in the Provigil (modafinil) augmentation study often cited. Here's the lineup:
> > > #1 Celexa (citalopram) and Wellbutrin (bupropion)
> > > #2 Wellbutrin and Deseryl (trazodone)
> > > #3 Celexa
> > > #4 Celexa
> > > #5 Wellbutrin, Depakote (divalproex), and Lamictal (limotrigine)
> > > #6 Serzone (nefazodone) and Paxil (paroxetine)
> > > #7 Effexor (venlafaxine)
> > >
> > > The attached link gives more patient details including age, diagnosis, previous meds, time to initial effect, and brief analysis.
> > >
> > > Rick
> > >
> > > http://alertpubs.com/august2000psych.htm#Stimulant Augmentation in Depression
>
>
>
>
>
>
> > I thought there was a known metabolic interaction between citalopram and modafinil?
> >
> > > >I don't know if it is relevant, but the majority of patients who responded in the small open-label study of modafinil-augmentation often cited were taking bupropion. I think this was more the result of patient selection than rate of response.
> > >
> > >
> > > - Scott
> > >
> > > >Clin Psychiatry 2000 May;61(5):378-81 Related Articles, Books
> > >
> > >
> > > >Modafinil augmentation of antidepressant treatment in depression.
> > >
> > > >Menza MA, Kaufman KR, Castellanos A.
> > >
> > >
> > > This may be even *less* relevant, but for the record there were 7 patients in the Provigil (modafinil) augmentation study often cited. Here's the lineup:
> > > #1 Celexa (citalopram) and Wellbutrin (bupropion)
> > > #2 Wellbutrin and Deseryl (trazodone)
> > > #3 Celexa
> > > #4 Celexa
> > > #5 Wellbutrin, Depakote (divalproex), and Lamictal (limotrigine)
> > > #6 Serzone (nefazodone) and Paxil (paroxetine)
> > > #7 Effexor (venlafaxine)
> > >
> > > The attached link gives more patient details including age, diagnosis, previous meds, time to initial effect, and brief analysis.
> > >
> > > Rick
> > >
> > > http://alertpubs.com/august2000psych.htm#Stimulant Augmentation in Depression
Posted by Elizabeth on October 30, 2001, at 23:05:55
In reply to Re: modafinil pharmacology » Elizabeth, posted by SLS on October 29, 2001, at 17:28:48
Scott,
Thanks for the info -- I always learn something from your posts. :-) But I really want to see the numbers on modafinil, and I'm finding it almost suspicious that it's been so difficult for me to find them. Sometime soon I will get around to going to the medical library and looking into this.
-elizabeth
Posted by jojo on November 2, 2001, at 22:11:10
In reply to Re: CA rocket fuel; modafinil pharmacology » JohnX2, posted by Elizabeth on October 28, 2001, at 10:36:21
I took Buprenex 0.3 mg. intrnasally, qid.
Severe crash after 6 weeks. It took 4-6 weeks of
Celexa, 20 mg./day (sometimes 40 mg.)to recover to
my previous acceptable state. Also, no relief
from anorgasmia during this time. I've seen a
report that anorgasmia persisted for greater than
2 months after discontinuation of gabapentin. I
stopped taking Saw Palmetto, 240 mg. extract/day,
and this seems to have helped, especially in the
first 2 weeks after stopping it. Not enough data
yet to say that Saw Palmetto was the cause of the
anorgasmia. I haven't seen any medical references
suggesting that it can be implicated in
anorgasmia, but I believe it blocks certain
androgen receptors in prostatic tissue.
This is the end of the thread.
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