![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 18 of 18. This is the beginning of the thread.
Posted by AndrewB on May 14, 2000, at 8:58:08
I would like to find an acceptable substitute for amineptine. It is a dopamine reuptake inhibitor. It seems like the only other D uptake inhibitors out there are cocaine and Mazindol. Is amineptine a somewhat stepped down version of cocaine that allows at low doses a mild long term psycho stimulation without rebound fatigue or withdrawal? Mazindol seems to be unacceptable. One report said that it caused significant anxiety and did not improve activity level.
There are a lot of amphetamine analogues and precursors out there. One called fencamfamine is listed as an antidepressant. Maybe something like this or even adderall would substitute somewhat for amineptine. Any ideas? Do all amphetamines type drugs cause tolerance and rebound effects?
AndrewB
Posted by PeterJ on May 15, 2000, at 1:27:33
In reply to Amineptine substitute? Peter J, Scott, posted by AndrewB on May 14, 2000, at 8:58:08
> I would like to find an acceptable substitute for amineptine. It is a dopamine reuptake inhibitor. It seems like the only other D uptake inhibitors out there are cocaine and Mazindol. Is amineptine a somewhat stepped down version of cocaine that allows at low doses a mild long term psycho stimulation without rebound fatigue or withdrawal? Mazindol seems to be unacceptable. One report said that it caused significant anxiety and did not improve activity level.
>
> There are a lot of amphetamine analogues and precursors out there. One called fencamfamine is listed as an antidepressant. Maybe something like this or even adderall would substitute somewhat for amineptine. Any ideas? Do all amphetamines type drugs cause tolerance and rebound effects?While there is no precise substitute for amineptine, amphetamine (e.g. Adderall) might be close. Ritalin is another option.
Tolerance and dependance are a potential problem with all amphetemine-like drugs. The individual response is variable. Some people respond to the same dosage for years, while others develop rapid tolerance. (I know of no way to predict responses, except one's previous response to simulants.)
Some psychiatrists have suggested that co-treatment with an antidepressant and a stimulant may produce a more lasting effect. A combination of desipramine with amphetamine or ritalin would be an example.
L-Deprenyl is also worth consideration for long term DA enhancement.
Peter
Posted by AndrewB on May 15, 2000, at 9:12:34
In reply to Re: Amineptine substitute? Peter J, Scott, posted by PeterJ on May 15, 2000, at 1:27:33
Thanks Peter. I'll ask KarenB how she compares adderall with amineptine.
Any reason to think a COMT inhibitor like Entacapone acts like amineptine? Entacapone increases dopamine in the synaptic cleft. It seems it may able to help people with depression and yet it can cause anxiety in some. Amineptine can relieve depression yet increase anxiety.
Posted by SLS on May 15, 2000, at 17:36:12
In reply to Re: Amineptine substitute? Peter, COMT inhibitor, posted by AndrewB on May 15, 2000, at 9:12:34
> Thanks Peter. I'll ask KarenB how she compares adderall with amineptine.
>
> Any reason to think a COMT inhibitor like Entacapone acts like amineptine? Entacapone increases dopamine in the synaptic cleft. It seems it may able to help people with depression and yet it can cause anxiety in some. Amineptine can relieve depression yet increase anxiety.--------------------------------------------------------------
Hi Andrew.
I spent some time earlier today looking into the pharmacology of various psychostimulants. It's hard to find one that would be similar enough to amineptine to choose as a candidate to replace it. If the idea is simply to look for a drug to increase the concentration of dopamine within the synaptic cleft, they are all eligible. Obviously, this property is not in and of itself sufficient to promote a long-lasting antidepressant effect.The one thing that differentiates amineptine from the stimulants is that it lacks the ability to increase the release dopamine into the synaptic cleft. Perhaps the property of stimulants to release dopamine explains why tolerance to their stimulating effects occurs and why their antidepressant effects are usually transient when used monotherapeutically.
In the mid 1980's, a drug named nomifensine (Merital) was marketed briefly as an antidepressant. It had been studied for many years, and its pharmacology was well documented. It worked well for many people. To my knowledge, it was the only other antidepressant besides amineptine that was a potent reuptake inhibitor of dopamine as well as being a norepinephrine reuptake inhibitor. Like amineptine, nomifensine does not increase the release of dopamine.
The only other marketed drug I could find that potently inhibits the reuptake of dopamine without promoting its release is mazindol. Mazindol also inhibits the reuptake of norepinephrine.
Amineptine, nomifensine, and mazindol have similar catecholaminergic pharmacological profiles and differ from stimulants and cocaine in that they do not promote the release of dopamine.
The inhibition of COMT in the synaptic cleft would spare dopamine, but it would not prevent this spared dopamine from being sucked back up by the presynaptic neuron, whereupon it is dismantled by MAO. In addition, the rate of reuptake would be increased, as the presynaptic neuron is induced to produce more transporter molecules. I think the inhibition of synaptic COMT would enhance dopaminergic neurotransmission, but not to the extent as would amineptine, nomifensine, or mazindol. It still might work, though. It is difficult to predict.
What have you found regarding the efficacy of entacapone as an antidepressant?
The few things that I've run across weren't too impressive. It makes a good adjunctive medication for treating Parkinson's Disease by prolonging the effect of levodopa, primarily through the inhibition of its break-down in the blood stream. I don't know to what degree COMT inhibition within the neuronal synapse influences the concentration of neurotransmitter there.
You mentioned that you didn't feel mazindol would make a good candidate to replace amineptine in the role of an augmenting agent to amisulpride due to its potential to produce anxiety. How does mazindol compare to the stimulants with regard to the incidence and magnitude of anxiety as a side effect?
Do you know of anyone who has added a stimulant to amisulpride, sulpiride, or Zyprexa?
- Scott
Posted by AndrewB on May 16, 2000, at 3:57:42
In reply to Re: Amineptine substitute? Peter, COMT inhibitor, posted by SLS on May 15, 2000, at 17:36:12
Scott,Excellent information. Thank you.
Perhaps you would benefit for minaprine (Cantor), supposedly a potent reuptake inhibitor of dopamine and serotonin. It soundsinteresting but I fear that I wouldn’t do well with anything that increases serotonin.
The only info I have on entacapone as an AD is the abstract that I posted in your previous thread on COMT inhibitors.
Mazindol doesn’t sound that good to me. I searchedthe net and couldn’t find any indication that it increased energy, arousal or mood. The study I mentioned before indicated it didn’t increase activity. It doesn’t seem to do any of the things one wants a psychostimulant to do. Also, I remember someone said that it made a person feel yucky.
I don’t know of anyone combining a stim to amisulpride or any other low dosed antipsychotic.
Posted by SLS on May 16, 2000, at 7:22:58
In reply to Re: Amineptine substitute? Scott, COMT inhibitor, posted by AndrewB on May 16, 2000, at 3:57:42
> Perhaps you would benefit for minaprine (Cantor), supposedly a potent reuptake inhibitor of dopamine and serotonin. It soundsinteresting but I fear that I wouldn’t do well with anything that increases serotonin.
Hey Andrew!It sounds like you found a good one.
Do serotonergic drugs actually worsen your depression?
- Scott
Posted by PeterJ on May 16, 2000, at 18:58:50
In reply to Re: Amineptine substitute? Scott, COMT inhibitor, posted by SLS on May 16, 2000, at 7:22:58
I can't always post as much as I'd like when I'm
feeling fatigued, but here are some further
observations on dopamine that may be helpful.1. It's not too clear what the difference between
releasers and uptake inhibitors is clinically.
Amphetamine does both. Cocaine inhibits DA uptake
but does not cause release. Both have very
similar behavioral effects.
The mechanism of amineptine depend on
which lab you believe. I've seen a studies that
say it increases DA release and others that say
it only inhibits uptake. I'm inclined to think
it is an uptake inhibitor only, based on its
large tricylic structure.
BTW, the dopamine transporter acts like a shuttle
that goes back and forth across the cell membrane.
When it crosses it can take a molecule of
dopamine with it. (Imagine one of those clotheslines
strung btween two buildings with a pulley. The
dopamine transporter is like a basket on the line.)
It can shuttle dopamine into or out of the cell,
depending on the situation.
If you give amphetamine, it binds to the shuttle
on the outside of the cell. The shuttle then
crosses over to the inside face of the membrane,
taking the amphetamine with it. The amphetamine
is released inside. Then some dopamine binds to the
now empty transporter and it is shuttled to the outside
of the cell.
A pure uptake inhibitor will bind to
the tranporter when it is on the outside surface of the
cell and put it in such a conformation that it is stuck
there and cannot cross back over. Thus it cannot shuttle
dopamine into the cell.
2. Mazindol has been studied in a PET study of
human subjects. The study intended to explore
its use as a treatment for cocaine addiction.
Typical doses of mazindol only
bound a very small percent of DA receptors. It
was felt that doses high enough to inhibit
DA receptors would have excessive side effects.
Mazindol seems to be about 20X more potent
at inhibiting NE uptake.
It has been reported to relieve
depression in a few cases, but that may
be due to its NE effects as much as its DA
effects.3.Long term l-deprenyl leads to the accumulation
of some unknown substances which block DA uptake. Thus
it may enhance DA activity both by MAO inhibition and
indirectly by uptake inhibition.4. St. John's Wort may have mild dopaminergic
effects.5. Niacinamide in high doses (500mg-3gms) may help somewhat
in dopamine depletion by stimulants. NADH, which
you can get also get OTC from some pharmacies
may also help.6. COMT inhibitors have theoretical interest, but
limited clinical experience in depression. Details
were discussed in another thread.7. Initial enhancement by many substances of
dopamine activity often results in only short-
lived benefits. Dr. Baron Shopsin, who
studied several dopamine drugs clinically in the
70s and 80s found this to be their achilles heel.8. Amineptine is one of the few antidepressants
to increase REM sleep. Bupropion is another, and
it may also have mild DA effects. It might be
worth trying.9. Direct DA agonists like piribidel, bromocriptine,
pramipexole, etc., may also help.Peter
Posted by SLS on May 17, 2000, at 8:32:24
In reply to Re: Amineptine substitute?, posted by PeterJ on May 16, 2000, at 18:58:50
Dear Peter,
I want to thank you for your concern and your detailed contribution here. I find it very relevant personally, as I will probably be exploring dopaminergic drugs in my treatment.
> Initial enhancement by many substances of
dopamine activity often results in only short-
lived benefits. Dr. Baron Shopsin, who
studied several dopamine drugs clinically in the
70s and 80s found this to be their achilles heel.
Dr. Shopsin was my doctor for a few years. I briefly served as one of his research assistants. He was one of Nathan Klein's protoges. He was brilliant. Unfortunately, he left town.He liked to use pemoline to augment other drugs, particularly Parnate.
Cocaine induces an increase in the release of dopamine in the nucleus accumbens. I am not sure as to how this occurs, but I have not yet seen an explanation that involves a action at the synapse. I guess it is more the result of its DA reuptake inhibition in afferent pathways.
- Scott
Posted by SLS on May 17, 2000, at 14:24:06
In reply to Re: Amineptine substitute?, posted by PeterJ on May 16, 2000, at 18:58:50
Thanks Peter.
> 1. It's not too clear what the difference between
> releasers and uptake inhibitors is clinically.
> Amphetamine does both.Amphetamine is considered to be a much more potent releaser of dopamine and norepinephrine than it is a reuptake inhibitor. From what I've read, it seems that it is its releasing effect that is given most of the credit for its clinical and biological activity.
> Cocaine inhibits DA uptake but does not cause release. Both have very similar behavioral effects.
Cocaine putatively promotes the release of dopamine in the nucleus accumbens. I don't know what mechanisms are responsible for this, but I haven't encountered anything that involves actions at the synapse. Perhaps it accomplishes this through activation of afferent pathways in a way similar to opiates. I guess this might occur as the result of norepinephrine reuptake inhibition by cocaine in the amygdala or hippocampus.
> The mechanism of amineptine depend on
> which lab you believe. I've seen a studies that
> say it increases DA release and others that say
> it only inhibits uptake. I'm inclined to think
> it is an uptake inhibitor only, based on its
> large tricylic structure.How is the release of neurotransmitter effected by a drug acting at the synapse differentiated from that which may be a result of pharmacological activity elsewhere. Perhaps some studies do not use a paradigm that would accomplish this effectively.
> BTW, the dopamine transporter acts like a shuttle
> that goes back and forth across the cell membrane.
> When it crosses it can take a molecule of
> dopamine with it. (Imagine one of those clotheslines
> strung btween two buildings with a pulley. The
> dopamine transporter is like a basket on the line.)
> It can shuttle dopamine into or out of the cell,
> depending on the situation.
> If you give amphetamine, it binds to the shuttle
> on the outside of the cell. The shuttle then
> crosses over to the inside face of the membrane,
> taking the amphetamine with it. The amphetamine
> is released inside. Then some dopamine binds to the
> now empty transporter and it is shuttled to the outside
> of the cell.
> A pure uptake inhibitor will bind to
> the tranporter when it is on the outside surface of the
> cell and put it in such a conformation that it is stuck
> there and cannot cross back over. Thus it cannot shuttle
> dopamine into the cell.
Much thanks! I did not know this.
I read that amphetamine promotes the release of norepinephrine via vesicular release.Does any of this happen at DA terminals?
Does amphetamine also promote the release of norepinephrine via NE transporter?I'm having you do my homework. :-)
> 2. Mazindol has been studied in a PET study of
> human subjects. The study intended to explore
> its use as a treatment for cocaine addiction.
> Typical doses of mazindol only
> bound a very small percent of DA receptors. It
> was felt that doses high enough to inhibit
> DA receptors would have excessive side effects.
> Mazindol seems to be about 20X more potent
> at inhibiting NE uptake.Any chance you could point me in the direction of some of this info? I find this quite disappointing.
> It has been reported to relieve
> depression in a few cases, but that may
> be due to its NE effects as much as its DA
> effects.I imagine all of these investigations studied mazindol as monotherapy. I would like to consider it as an adjunct to things like amisulpride or an MAO inhibitor. DA agonists and amphetamines are also usually ineffective at treating depression monotherapeutically, but are often good augmenting agents to antidepressants (I hope).
> 7. Initial enhancement by many substances of
> dopamine activity often results in only short-
> lived benefits. Dr. Baron Shopsin, who
> studied several dopamine drugs clinically in the
> 70s and 80s found this to be their achilles heel.Do you mean "enhancement" of an antidepressant effect during ongoing antidepressant therapy? This seems to have been my experience with Dexedrine and Parlodel.
Baron Shopsin was my doctor for almost four years. I did some work for him as a research assistant. He was quite fond of pemoline as an augmenting agent, particularly with Parnate. He also liked to use Pirebedil, then known as ET-495. Dr. Shopsin was a disciple of Nathan Klein. He had a keen mind and was ahead of his time. He was one of the first to conclude that schizo-affective disorder was a discreet illness, and wrote a book about it (of which he was quite proud). He was also the first investigator to recognize that Wellbutrin carried less liability to induce mania. Unfortunately, he moved his practice out to the Old Brickyard.
> 9. Direct DA agonists like piribidel, bromocriptine,
> pramipexole, etc., may also help.I am trying to decide which of these I would like to use. Pergolide is also a candidate. Any thoughts?
Thanks again.
Sincerely,
Scott
Posted by PeterJ on May 17, 2000, at 17:40:38
In reply to Re: Amineptine substitute?, posted by SLS on May 17, 2000, at 14:24:06
> Amphetamine is considered to be a much more potent releaser of dopamine and norepinephrine than it is a reuptake inhibitor. From what I've read, it seems that it is its releasing effect that is given most of the credit for its clinical and biological activity.I wouldn't argue with that, except to say that the way it causes release--by binding to the dopamine shuttle and moving into the cell--inherently blocks uptake at the same time. So it's not a simple matter to separate the two effects. For example, in a cell already releasing larger amounts of dopamine it might act mainly by inhibiting uptake, but in a cell not releasing dopamine to start with its greateest effect would be release.
> How is the release of neurotransmitter effected by a drug acting at the synapse differentiated from that which may be a result of pharmacological activity elsewhere. Perhaps some studies do not use a paradigm that would accomplish this effectively.
In a whole brain study, enchanced release and reuptake inhibition are very hard to distinguish. They both result in more dopamine outside the cell. The best way to determine the actual moleculer effect is to study binding to the transporter in in vitro systems, such as cloned cells expressing the transporter gene.
> I read that amphetamine promotes the release of norepinephrine via vesicular release.
>
> Does any of this happen at DA terminals?
> Does amphetamine also promote the release of norepinephrine via NE transporter?
>
> I'm having you do my homework. :-)This reference should be helpful:
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10193907&dopt=Abstract
> > 2. Mazindol has been studied in a PET study of
> > human subjects. The study intended to explore
> > its use as a treatment for cocaine addiction.
> > Typical doses of mazindol only
> > bound a very small percent of DA receptors. It
> > was felt that doses high enough to inhibit
> > DA receptors would have excessive side effects.
> > Mazindol seems to be about 20X more potent
> > at inhibiting NE uptake.
>
> Any chance you could point me in the direction of some of this info? I find this quite disappointing.http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9676890&dopt=Abstract
The one ray of hope is that the study was done in cocaine addicts, and they may have elevated levels of the dopamine transporter. Perhaps in non-addicts mazindol would look better.
> > It has been reported to relieve
> > depression in a few cases, but that may
> > be due to its NE effects as much as its DA
> > effects.
>
> I imagine all of these investigations studied mazindol as monotherapy. I would like to consider it as an adjunct to things like amisulpride or an MAO inhibitor. DA agonists and amphetamines are also usually ineffective at treating depression monotherapeutically, but are often good augmenting agents to antidepressants (I hope).It's worth a try. Just be cautious of its NE effects re hypertension, anxiety etc.
>
> > 7. Initial enhancement by many substances of
> > dopamine activity often results in only short-
> > lived benefits. Dr. Baron Shopsin, who
> > studied several dopamine drugs clinically in the
> > 70s and 80s found this to be their achilles heel.
>
> Do you mean "enhancement" of an antidepressant effect during ongoing antidepressant therapy? This seems to have been my experience with Dexedrine and Parlodel.I meant enchancement over baseline DA activity, i.e. as monotherapy. Adjunctive use has a better record as you know, although even there, the more specfic DA effects may often fade with time.
> Baron Shopsin was my doctor for almost four years. I did some work for him as a research assistant. He was quite fond of pemoline as an augmenting agent, particularly with Parnate. He also liked to use Pirebedil, then known as ET-495. Dr. Shopsin was a disciple of Nathan Klein. He had a keen mind and was ahead of his time. He was one of the first to conclude that schizo-affective disorder was a discreet illness, and wrote a book about it (of which he was quite proud). He was also the first investigator to recognize that Wellbutrin carried less liability to induce mania. Unfortunately, he moved his practice out to the Old Brickyard.By "Old Brickyard" do you mean Indianapolis? Or is this a metaphor with which I am unfamiliar?
Pemoline is an excellent DA releasing drug. Very selective. No effect on NE, thus no concern about hypertension w/ MAOIs. Unfortunately fewer doctors are prescribing it since the FDA sent out a "Dear Doctor" letter warning of liver toxicity. The thing is, liver toxicity from pemoline is very rare in adults. For children with ADHD it can be problematic.
> > 9. Direct DA agonists like piribidel, bromocriptine,
> > pramipexole, etc., may also help.
>
> I am trying to decide which of these I would like to use. Pergolide is also a candidate. Any thoughts?I'm not sure which would be best, but a direct agonist is worth trying.
One more thought: DA is also taken up by the NE transporter (i.e. on nearby NE terminals) so blocking the NE transporter may enhance the effects of DA release/uptake inhibition in some areas.
Peter
Posted by AndrewB on May 18, 2000, at 16:05:34
In reply to Re: Amineptine substitute?, posted by PeterJ on May 17, 2000, at 17:40:38
From CHRONIC FATIGUE SYNDROME ASSOCIATION OF LONG ISLAND
NEW DRUG BENEFITS CFIDS!
A newly approved drug for Parkinson's disease is a real help for PWCs, said
Dr. Jay A. Goldstein. If it continues to be as useful as the initial PWCs have
found it, it could very well join his first five or six drugs in his treatment
protocol.The new class of drug, called catechol-O-methyltransferase inhibitors (COMP),
helps both cognition and energy. You will know after just one 100-mg pill if
this treatment is effective for you. Dr. Goldstein is now prescribing 100 mg
twice daily for those who find benefits from the medication.Toleopone, with the common name of Tasmar got USA clearance just this past
May. In Europe, a similar drug is available called Comtess. It is not as powerful
as Tasmar, however. In the US, Comtess is called Comtan. Tasmar is a much
more potent inhibitor of COMT and penetrates better into the brain. There do not
seem to be any adverse side effects from this medication. The drug has been
written up favorably in the April 25th, 1998 edition of The Lancet (Vol. 351)
but of course, refers only to Parkinsonian patients. You may want to request
that your physician give you a prescription for just one pill to see if it benefits
your energy and cognition."Tasmar is more effective (immediately) when combined with a dopamine
agonist such as Requip (quinpirol) or a reversible inhibitor of monoamine
oxidose (RIMA) such as medlobemide, which due to the wisdom of the FDA, is
available in every industrialized country in the world but the USA! When it
works, it's quite energizing," said Dr. Goldstein.The preceding was reported in The National Forum - Summer 1998.
----------------------------------------
Dr. Jay Goldstein on Tasmar from his website:Tasmar (Tolcapone): Neither an exotic location on the Silk Road nor a
Mafia-run turnpike in Chicago, Tasmar is a unique agent. It inhibits the enzyme
catechol-ortho-methyltransferase (COMT), one of the two enzymes (monomine
oxidase is the other) that metabolizes NE and DA. Tasmar degrades them in the
synaptic cleft. I have been waiting for this drug for years. It is marketed for
Parkinson's disease, and most physicians have not heard of it yet. It can work
as monotherapy, either acutely or after four weeks or so. It may be more
effective (immediately) when combined with a dopamine agonist such as Requip
(quinpirole) or a reversible inhibitor of monoamine oxidase (RIMA) such as
meclobemide, which due to the wisdom of the FDA is available in every other
industrialized country in the world but the USA. The package insert advises
against combining it with irreversible MAOIs such as Nardil and Pamate, so I
have not done so. This combination would leave reuptake as the only
mechanism to terminate the post-synaptic effect of catecholamines, although rats
do quite well on the two drugs. Tasmar is in the top 10 ",Arith a bullet." An
accountant, unable to work for three years, is back to work now on
meclobemide and Tasmar. Adding Sinemet may enhance the action of Tasmar,
since it is metabolized to dopamine. Sinemet may be given instead of Requip or
Mirapex, or concomitantly. Requip and Mirapex are useful in that they are D3
agonists also. The D3 receptor is located primarily in the limbic system. Since
COMT is a methyl group acceptor, it may work better by combining it with
S-adenosylmethionine (SAMe), a methyl group donor with no ADRs, effective
in FMS and depression. SAMe is available in many other countries, and certain
buyer's clubs will supply you with it. Tasmar inactivates COMT, allowing
SAMe to transfer methyl groups to precursors so that more norepinephrine can
he formed. This process is termed "transmethylation" and is too complicated to
discuss further in this column. Interested readers may consult the work of John
R. Sinythies and R.J. Baldessarini and go from there.
------------------------------------------Notes:
1) Medlobemide should read, I believe, moclebemide. Do not combine COMTs
with standard MAOIs.2) I presume that a COMT, since it is more effective with Requip (a D2-3
dopamine agonist), would be more effective when combined with amisulpride
or Mirapex.3) Check out Dr. Jay Goldstein’s website (http://www.drjgoldstein.com/) on
Chronic Fatigue Syndrome for other info. that is relevant to dopamine
enhancement and med. that may be able to help with fatigue in depressive
syndromes. Note especially the article entitled, “Tiptoe Through the
Treatments”.
4) I am going to order Entacapone and take a trial of it.5) Tasmar can cause liver toxicity. Dr. Jay Goldstein no longer prescribes it
without bimonthly liver tests.NEW WARNINGS FOR PARKINSON'S DRUG, TASMAR>
FDA and Hoffmann-La Roche Inc., the manufacturer of the drug for patients
with Parkinson's Disease, are advising doctors about reports of a new finding
of fatal liver injury associated with use of the drug, and recommending
significant changes in how it is used. Because of these reports, labeling now
states that the drug should be reserved for use only in patients who do not have
severe movement abnormalities and who don't respond to or who are not
appropriate candidates for other available treatments.Hoffmann-La Roche is issuing a "Dear Doctor" letter alerting physicians to the
labeling changes and reports of three deaths from acute, severe (fulminant) liver
failure.Although a precise rate of these deaths is not known, about 60,000 patients
have been given worldwide, indicating a rate of approximately one reported
death for every 20,000 patients using the drug. FDA and Hoffmann-La Roche
are asking health professionals to exercise additional caution in using the
product and to report any additional cases of liver injury.Tasmar> was originally approved as an adjunct to levodopa and carbidopa for
the treatment of the signs and symptoms of idiopathic Parkinson's disease.FDA advises doctors to follow instructions in the new boxed warning in the
drug's label. The warning calls for increased liver monitoring (every two
weeks) if a prescriber elects to treat patients with . Doctors should also advise
their patients to self-monitor for classical signs of liver disease such as jaundice
and nonspecific ones such as fatigue and loss of appetite. The boxed warning
also advises that in light of the severe liver toxicity, if a patient fails to show a
substantial clinical benefit within the initial 3 weeks of treatment, he/she should
be withdrawn from the drug.In addition, the new labeling includes an informed consent document that
physicians are advised to use when prescribing to patients to help assure full
understanding by patients of the potential benefits and risks of this product.Patients are advised not to stop taking without first speaking to their doctor or
health care provider. Abrupt withdrawal or reduction in dose can lead to a return
of symptoms or to other more serious complications.FDA is closely monitoring this matter and may take further action if new reports
show that the liver injury rate proves greater than it now appears.
Posted by SLS on May 18, 2000, at 16:56:38
In reply to Re: COMTs as substitutes, posted by AndrewB on May 18, 2000, at 16:05:34
Hi Andrew.
Please keep us informed as you progress through your trial of entacapone. I hope you get out of it what you are looking for. Although it hasn't seemed to be very potent as an antidepressant when used monotherapeutically, it looks like a good drug to combine with the other dopaminergics that you mention. Combining entacapone with amisulpride is an intriguing proposition. One other strategy mentioned by PeterJ was to add l-dopa (Sinemet) to a COMT inhibitor.Q: You seem to be experimenting with quite a few drugs. Have you ever felt satisfactorily well on any drug regimen? What residual symptoms have not been adequately treated?
Perhaps Cam W. can comment on any drug interaction concerns with the use of entacapone.
I am eager to hear that you do well on your new adventure. Good luck!
Oh, I almost forgot. My doctor told me yesterday that Sanofi-Synthelabo is now intested to bring amisulpride to the U.S.
Sincerely,
Scott
Posted by AndrewB on May 18, 2000, at 17:51:28
In reply to Re: COMTs as substitutes, posted by SLS on May 18, 2000, at 16:56:38
What am I still trying to deal with, why the continual experimentation? Social anxiety/confidence. Amisulpride makes it better. Amineptine is able to pretty much take my self doubts away. Amineptine however isn't made anymore and, even if I could hoard a huge supply, I don't know if amineptine's effects on social anxiety are sustainable or without a rebound effect. My initial impression is I have to take frequent drug holidays from it. Good idea to ask Cam about any drug interactions. Dr. Goldstein also mentions combining Sinemet with the COMT.
Posted by SLS on May 19, 2000, at 13:01:15
In reply to Re: COMTs as substitutes, posted by AndrewB on May 18, 2000, at 17:51:28
> What am I still trying to deal with, why the continual experimentation? Social anxiety/confidence. Amisulpride makes it better. Amineptine is able to pretty much take my self doubts away. Amineptine however isn't made anymore and, even if I could hoard a huge supply, I don't know if amineptine's effects on social anxiety are sustainable or without a rebound effect. My initial impression is I have to take frequent drug holidays from it. Good idea to ask Cam about any drug interactions. Dr. Goldstein also mentions combining Sinemet with the COMT.
Amineptine may be acting sort of like cocaine or amphetamine, fostering a short-lived superficial increase in self-confidence. However, I know from personal experience that my self-confidence and social-anxiety improve upon remission of depression.I am not a big fan of "pulsing" antidepressants. It can induce mania in vulnerable individuals (apparently not a concern) and reduce one's responsivity to them. This is not to say that you are not doing exactly the right thing for yourself. I just wanted to mention it.
Perhaps this is a problem area that is not located in the brain.
I find that a behaviorist approach can be helpful. (Cognitive behaviorism).
Continued good luck. I'm routing for you.
- Scott
Posted by AndrewB on May 19, 2000, at 16:05:10
In reply to Re: Amineptine substitutes - Andrew, posted by SLS on May 19, 2000, at 13:01:15
Thank you Scott, your input really helps.
I been having thinking about some of the things you just mentioned. Would cognitive therapy help? Do I have remaining depression that I don't recognize that limits my passion/self esteem/ confidence. During my trial of Mirapex (without amisulpride) I just wrapped up, I got so depressed. I'm still depressed. With the depression came back my vicious self loathing that made me unable to face the world. My self esteem seems tied up with my mood.
I'm been wondering whether I've missed something with serotenergic agents. Have I given them enough of a trial. I have only taken Serzone, who is to say that another serotenergic wouldn't help. Inspired by John L's experience with St. Johns, I've started a St. John's trial today (along with restarting amisulpride). I read a whole bunch of posts from other sites from people who were helped by St. Johns. It seems to help mostly those who had a mood response to an SSRI or Serzone but couldn't stand the side effects. St. Johns seems blessedly side effect free. But anyway, I never recieved ANY mood response from Serzone, so I'm not that hopeful that St. Johns will help. It seems prudent however to give another serotnergic agent a try and this is the easiest one to do.
YES, YES- amineptine may increase confidence and enthusiasm only temporarily like speed or cocaine--like an induced mania that is not sustainable. It apparently can improve energy and probably mood over the long run but confidence and what not may be transitory. I may be just chasing the dragon here. The whole point is moot anyway though. I've just got a limited supply of amineptine and therefore I should just use it when I'm very worn down or in a paticularly challenging situation- Right?? Anyway I'll see if the entacapone helps me any. It should arrive in three weeks.
I have new insurence that pays for mental so maybe I'll start regular cognitive therapy. It mightwork better than borrowing some rat's blood!
Looking at your history with dopamine I wondered if there was any dopaminergic you wouldn't poop out on. What do you think. Maybe Peter J has got some ideas on what could combat poop out. Dr. Goldstein mentioned sinemet and SAMe as providing facilitation of entacapone. It seems like someone who really understood dopamine biochemistry might know what to suggest to you.
Have you looked at Goldstein's site yet. Any comments?
AndrewB
Posted by AndrewB on May 20, 2000, at 2:53:27
In reply to Re: Amineptine substitutes - Andrew, posted by AndrewB on May 19, 2000, at 16:05:10
Scott,
Thought I would let you know that Dr. Goldsteins book, which I haven't read, has a chapter on receptor desensitization and drug tolerence. Apparently he has some strategies (i.e. using inositol?) for dealing with receptor desensitization. This may be relevant to you because he deals a lot with the dopamine receptors.
AndrewB
Posted by AndrewB on May 20, 2000, at 3:27:26
In reply to Re: Tolerence, Scott, posted by AndrewB on May 20, 2000, at 2:53:27
Dr. Goldstein's website mentions the use of oxytocin. Possibly he uses this to prevent dopamine drug tolerence. See the website below. Make sure to check out the links. Oxytocin is available as a sinus spray.
http://www.oxytocin.org/oxy/oxydrug.html
Posted by SLS on May 20, 2000, at 15:47:32
In reply to Re: Amineptine substitutes - Andrew, posted by AndrewB on May 19, 2000, at 16:05:10
Dear Andrew,
I hope you are feeling a bit better today.I wanted to write just to offer some comfort and support.
I wouldn't want to comment at this point on the desirability for you to receive psychotherapy. I just would like to say that having a healthy brain does not guarantee having a healthy mind. The mind is a dynamic entity. I am always seeking to improve the way I interact with myself and my constantly changing environment. It is a skill that can be developed.
The depressive state produced by autonomous anomalies of physiology alters the workings of the mind. You already know this. It very difficult, perhaps impossible for some, to separate the biological from the psychological as they are inextricably linked. The potential to successfully address the psychological, emotional, and behavioral is limited by the alterations of the conscious state produced by depression. If one is refractory to treatment and must endure such a depressed state, they have no better option than to attack their psychological issues despite it. For you, this is not entirely the case.
Your conscious state is alterable by the drugs you now have in your possession. I recommend that you first optimize your biological state before you attempt to evaluate and treat the psychological (should you feel the need to). For now, I would just look to recover the best antidepressant response you know how to achieve, and make stability your immediate goal. Don't worry too much yet about how much residual dysthymia, social anxiety, or other features of depression/fatigue that will remain. You will be in a better position to decide how to deal with it once you are out of the darkness and recover your good judgment.
Reboxetine + amisulpride
No amineptine.
St. John's Wort sounds good. I am eager to find out how you respond to it. I would think it a good potentiator of amisulpride.
I have some thoughts regarding you Mirapex experience, but I'll leave that for some future correspondence.
You can write me if you want to.
There is no need for you to feel disparate.
Please get well.
Sincerely
Scottsl.schofield@worldnet.att.net
This is the end of the thread.
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