![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 17 to 41 of 41. Go back in thread:
Posted by KarenB on April 23, 2000, at 18:09:19
In reply to Re: Q for KarenB, posted by KarenB on April 23, 2000, at 17:13:22
Hey Everyone,
I just e-mailed Servier, the manufacturer of Survector to ask them if they are still producing ANYWHERE in the world and where I could purchase it.
I'll let you know what I find out.
Karen
Posted by AndrewB on April 23, 2000, at 20:17:10
In reply to Re: What up w/Amineptine??, posted by KarenB on April 23, 2000, at 18:09:19
Karen,
That was a very good idea to email Servier. That ought to give us a definitive answer.
You asked about substitutes for sulpiride that are US available. Mirapex might have a similar effect. Myself, I would just order the sulpiride or amisulpride from overseas since they are cheaper than Mirapex.
Let me know if adderall is similar to aminpetine.
AndrewB
Posted by micahel on April 23, 2000, at 21:56:55
In reply to Re: What up w/Amineptine??, posted by KarenB on April 23, 2000, at 18:09:19
> Hey Everyone,
>
> I just e-mailed Servier, the manufacturer of Survector to ask them if they are still producing ANYWHERE in the world and where I could purchase it.
>
> I'll let you know what I find out.
>
> KarenGood idea Karen - I couldn't find an e-mail address for them - well done. Looking forward to hearing what they say. Btw - if you need any assistance w/french, let me know. michael
Posted by PeterJ on April 25, 2000, at 3:44:51
In reply to Re: Amineptine: what does this mean: Scott, CamW, posted by Scott L. Schofield on April 21, 2000, at 17:23:39
May I add a few comments to Scott's excellent response.
(I am sure Scott knows all this, but it's an interesting topic.)Many antidepressants down-regulate beta-adrenergic receptors
by inhibiting NE uptake and thus increasing NE levels at the synapse.
However, other antidepressants may down-regulate beta receptors by
more indirect means. For exampe sulpiride down regulates beta
receptors. This is believed to occur because it blocks pre-synaptic
dopamine heteroreceptors on NE neurons. The DA receptors inhibit
NE release so blocking them may increase NE release.
The most important indirect effect on NE receptors occurs via
the serotonin system. Most, if not all, SSRIs (there is some variation
among studies) down-regulate beta adrenergic receptors after chronic
administration in animals. If you lesion the serotonergic system, this
down-regulation does not occur. What is even more interesting is that
serotonergic lesions also prevent the down-regulation produced by
noradrenergic antidepressants such as desipmramine and other TCAs.
It appears that 5-HT2 receptors have a necessary role in the
regulation of beta adrenergic receptors.
One antidpressant which still produces beta receptor down-
regulation in serotonin lesioned animals is clorgyline. It is
hypothesized that clorgyline has such a powerful effect on serotonin
levels that it overcomes the effect of the lesions of the sertonin
system (Aulakh et al. Role of serotonergic input in the down-regulation
of beta-adrenoceptors following long term clorgyline treatment.
Eur J Pharmacol 1988 Oct 26;156(1):63-70)
ECT and Transcranial Magnetic Stimulation also down-regulate
these receptors.
Early on (1975) it was proposed that beta adrenergic down-regulation
was a common factor in all effective antidepressant treaments. This may
not be the case as at least one antidepressant does not seem to down-
regulate beta receptors--bupropion. It is still true, however that almost
all effective antidepressants down-regulate beta adrenergic receptors in
rats. It's assumed this happens in humans as well, but we really don't know.Peter
Posted by Cam W. on April 25, 2000, at 6:41:00
In reply to Beta Receptor Down-Regulation, posted by PeterJ on April 25, 2000, at 3:44:51
Peter - Nice expalanation. Downregulaton of beta receptors may be a step in normalizing CRH release by hypothalamic cells by decreasing CRH's gene expression. But then again, all antidepressants, except citalopram, modify glucocorticoid receptor responsivity to cortisol (or corticosterone in animal models). Celexa (citalopram) modifies mineralocorticoid receptor responsivity to cortisol. Anyway, all seem to "re-couple" the HPA axis, the body's main stress response system and resolve the symptoms of depression.I believe that the area of breakdown of the HPA axis (or closely linked systems - eg endorphin system) determines which antidepressant will "resplice" the appropriate dysconnection of the HPA axis (eg desipramine or reboxetine for norepinephrine dysfunction; clomipramine or SSRIs for serotonin dysfunction. - Cam W.
Posted by AndrewB on April 25, 2000, at 13:19:25
In reply to Beta Receptor Down-Regulation, posted by PeterJ on April 25, 2000, at 3:44:51
Peter,
Thank you Peter for your excellent explanation of beta receptor down-regulation. It seems that the physiological changes to neurotransmitter neurons due to down-regulation are used by researchers as evidence of increased neurotransmitter receptor stimulation when trying to determine the actions (direct or indirect) of a drug or another neurotransmitter.
I hope you can answer my questions, I’m wondering if tolerance to a drug ever occurs due to down-regulation. Specifically I’ve read that tolerance to amphetamines is due to down-regulation of the alpha and beta andrenergic receptors due constant innervation of the post synaptic receptors. But I also have read a contradicting explanation for amphetamine tolerance. This explanation says amphetamine promotes the release of NE from nerve endings, specifically the cytoplasmic stores of NE. Tolerance in this scenario develops because only a limited amount of NE is available in this ‘mobile pool’. Which of these explanations sounds correct?
I realize that with SSRIs you don’t need ever increasing doses, so whatever down-regulation they create doesn’t cause tolerance. However if you stop taking an SSRI, are some people going to feel more depressed than ever before because their serotonergic and adrenergic systems have been down-regulated.
The reason I’m asking these questions is because I am trying amineptine. It is a dopamine reuptake blocker and is classified as a mild psychostimulant. I am wary of any psychostimulant causing tolerance. Amineptine is able to sharpen one’s mind among other things, but today I have not taken amineptine and I feel foggy headed. My mind is less sharp than it was before I started amineptine. Is this fogginess due to down-regulation (of either the dopaminergic or NE system). Can drug holidays counteract tolerance. If so, is there any standard protocol for the timing and spacing of drug holidays.
Thank you very much,
AndrewB
Posted by Scott L. Schofield on April 25, 2000, at 23:11:41
In reply to Beta Receptor Down-Regulation, posted by PeterJ on April 25, 2000, at 3:44:51
Dear Peter,
You couldn't possibly be more wrong. :-)> (I am sure Scott knows all this, but it's an interesting topic.)
I didn't. But I do now. Thank you for this wonderfully lucid explanation.
> One antidepressant which still produces beta receptor down- regulation in serotonin lesioned animals is clorgyline. It is hypothesized that clorgyline has such a powerful effect on serotonin levels that it overcomes the effect of the lesions of the sertonin system.Q: What is the proposed mechanism here? Are these chemical lesions? Do these lesions interfere with vesicular release, but spare postsynaptic processes? Is serotonin released passively from serotonergic nerve terminals? Does this serotonin stimulate nerves along the lesioned pathway to fire via local synapses, or does it migrate interstitially to remote sites?
I took clorgyline for about a year through an IND protocol administered by the NIMH of the National Institutes of Health. It is an amazing drug. It is arguably the most effective antidepressant in the world, and certainly the most potent MAO-inhibitor. Dr. William Potter and his colleagues considered it to be their "ace-in-the-hole" when treating refractory cases. As monotherapy, I found that it exerted the strongest persistant antidepressant effect of any drug I have taken. Unfortunately, I was only partially responsive, and was not permitted to combine it with anything else as per the protocol. My doctor was understandably reluctant to add desipramine, which I considered to be my best prospect. I wish I had forced the issue.
Clorgyline was never available as a pharmaceutical anywhere in the world. I don't know why. It had two things going for it as an antidepressant for treatment-resistant cases. It is extremely selective for MAO-A and it is irreversible. I spoke to a couple of doctors at the NIMH last week regarding its availability. I wanted to use it again and twist my doctor's arm to augment it with other antidepressants. Who knows, maybe having Lamictal on-board would have done the trick. I was informed that the chemical company that manufactures clorgyline no longer produces a preparation for human consumption. The three people who had been maintained on it for over a decade were forced to discontinue it. It remains available for animal experiments.
Crap.
The previous word is a very poor expletive for conveying excruciatingly painful emotions. I am very afraid.
- Scott
Posted by PeterJ on April 26, 2000, at 1:46:17
In reply to Re:Down-Regulation and Tolerance: Qs for PeterJ, posted by AndrewB on April 25, 2000, at 13:19:25
The greatest NE and 5-HT receptor changes produced by antidepressant
drugs appear to take place during the first few weeks of drug use, which
is coincident in time with the initial therapeutic effect. While later
changes can occur and might be associated with loss of antidepressant
effect ("poop out") this is not typical. Some depressed persons do
tend to develop tolerance in this way and thus don't respond well
to antidepressants. (Curiously, they may also improve transiently
during drug withdrawal.)With DA, the story is different. DA drugs tend to produce more rapid
beneficial effect, however it has been clinically observed that loss
of benefit with continued use is also more common. It's not inevitable
-- many people benefit from DA drugs for years -- but it can occur.The reason for tolerance to DA drugs is complex and not fully understood.
In the late 80s, Gold and others advocated the catecholamine depletion
explanation. I don't think this has been conclusively disproven, but
recent research has concentrated on receptor changes. These however
are very complex and dependant on the exact schedule of drug
administration.Chronic treatment of rats with stimulants may produce post-synaptic
DA receptor sensitization (kindling) or desensitization (tolerance).
Intermittent administration tends to sensitize while continuous
administration tends to lead to tolerance.Another newly revealed source of tolerance to DA drugs is super-
senisitivity of pre-synaptic DA autoreceptors (D2). These super
sensitive receptors inhibit DA output during the drug withdrawal
period.It's not clear why this supersensitivity develops.
In the case of Amineptine, if the initial benefit is dopaminergic, then
tolerance to that benefit is a theoretical concern. As I said, it's
not inevitable, but if you think you are observing tolerance, then
you may be right.Drug holidays might help, but there is no standard protocol for this.
Some patients with narcolepsy use drug holidays, but they are usually
pretty miserable during the "holiday". Your own observations
may be the best guide.Intermittent use may produce sensitization. This may be good--if
sensitization to the benefits occurs. On the other hand, sensitization
to adverse effects of DA (irritiablity, psychosis) may also occur, which
is not so good.If pre-synaptic DA supersensitivity is the problem, then sulpiride, which
blocks those receptors, would be ideal. The use of amineptine +
sulpiride ,which some have suggested on this board, makes perfect sense.
On the other hand, if you observe withdrawal symptoms from amineptine alone,
then withdrawal from amineptine + supliride may be a double whammy.Finally, despite my cautions about amineptine, I think it verges on a
crime against humanity to remove it from production when there are
at least some people who might benefit from it who have not responded
to other drugs.Peter
Posted by PeterJ on April 26, 2000, at 1:57:52
In reply to Re: Beta Receptor Down-Regulation, posted by Scott L. Schofield on April 25, 2000, at 23:11:41
>
> > One antidepressant which still produces beta receptor down- regulation in serotonin lesioned animals is clorgyline. It is hypothesized that clorgyline has such a powerful effect on serotonin levels that it overcomes the effect of the lesions of the sertonin system.
>
> Q: What is the proposed mechanism here? Are these chemical lesions? Do these lesions interfere with vesicular release, but spare postsynaptic processes? Is serotonin released passively from serotonergic nerve terminals? Does this serotonin stimulate nerves along the lesioned pathway to fire via local synapses, or does it migrate interstitially to remote sites?The lesions are produced by 5,7-dihydroxytryptamine which destroys serotonergic axons.
It is believed that clorgyline boosts the remaining levels of serotonin, but it is not
kown for sure if this is due to a small number of surviving axons or due to diffusion
of serotonin from other sites.
> I took clorgyline for about a year through an IND protocol administered by the NIMH of the National Institutes of Health. It is an amazing drug. It is arguably the most effective antidepressant in the world, and certainly the most potent MAO-inhibitor. Dr. William Potter and his colleagues considered it to be their "ace-in-the-hole" when treating refractory cases. As monotherapy, I found that it exerted the strongest persistant antidepressant effect of any drug I have taken. Unfortunately, I was only partially responsive, and was not permitted to combine it with anything else as per the protocol. My doctor was understandably reluctant to add desipramine, which I considered to be my best prospect. I wish I had forced the issue.
>
> Clorgyline was never available as a pharmaceutical anywhere in the world. I don't know why. It had two things going for it as an antidepressant for treatment-resistant cases. It is extremely selective for MAO-A and it is irreversible. I spoke to a couple of doctors at the NIMH last week regarding its availability. I wanted to use it again and twist my doctor's arm to augment it with other antidepressants. Who knows, maybe having Lamictal on-board would have done the trick. I was informed that the chemical company that manufactures clorgyline no longer produces a preparation for human consumption. The three people who had been maintained on it for over a decade were forced to discontinue it. It remains available for animal experiments.
>
> Crap.
>
> The previous word is a very poor expletive for conveying excruciatingly painful emotions. I am very afraid.
>
>
> - ScottYour frustration is understandable. There ought to be some kind of
provision that allows people who have not responded to standard
medications access to experimental chemicals. I am sure you
would be willing to sign a waiver saying the responsiblity
was yours if you could only try it. The situation now is...
well, you put it best...crap.Peter
Posted by AndrewB on April 26, 2000, at 11:07:18
In reply to Re:Down-Regulation and Tolerance: Qs for PeterJ, posted by PeterJ on April 26, 2000, at 1:46:17
Peter,
Thank you very much for your answers to my questions. They werre better answers than I could have hoped for. I am truly grateful for the opportunity to ‘talk’ with someone as informed as you are. I am fascinated about issues concerning dopamine potentiation , especially D2-D3 potentiation. I hope you will be able to answer these further questions. I have limited my questions to just those that are important to my condition at this time.
1) Are there rough equivalents to amineptine. For example, are COMT inhibitors possibly substitutes since they would result in increased dopamine in the synaptic clefts as does amineptine. By the way, does it seem like COMT inhibitors have AD potential either alone or in combo with an MAO-A, MAO-I or L-Dopa.
2) Can tyrosine supplementation potentiate the effect of amineptine. One person stated that tyrosine potentiated dexadrine by preventing dopamine depletion. Amphetamines like dexadrine are D2 reuptake blockers. Amineptine has similar mechanics, being a dopamine reuptake blocker.
3) Is it important to use a dopamine neuron neuroprotective agent such as pramipexole (a D2 agonist) when using agents such as amineptine that raise dopamine levels. Pramipexole may provide its neuroprotective effects through the depression of dopamine metabolism, antioxidant effects and the stimulation of trophic activity.
4) Is it possible for exercise to deplete dopamine and NE stores. After hard exercise, when unmedicated, I experience extreme mental fatigue following exercise. It starts maybe 12 hours (the next morning) after the exercise and lasts for maybe three days after that. Symptoms include loss of memory, mental confusion, busy head (increased internal dialogue, often self critical), lack of vigilance, physical fatigue, irritability, dysphoria, feelings of vulnerability, feelings of indecision, tiredness, spots and worms (floaters) in visual field sometimes accompanied by vertigo and mild orthostatic hypotension. It can get so bad that I’m not able to remember my own phone number or do simple number tasks. NE and dopamine (especially D2,D3) receptor transmission enhancers such as amisulpride and reboxetine are able to completely take away these symptoms except for the muscle soreness. The muscle soreness is taken away by high doses of 7-keto DHEA.
5) Does D1 receptor stimulation potentiate D2 receptor function. Does serotonin potentiate D2 receptor function. There is apparently a complex interrelationship of potentiation and inhibition between different dopamine receptors. Also, it is thought that part of the AD effect of serotenergic ADs is due to enhancement of D2 function.
Sorry to ask so many questions. They all however are so important to me.
Sincerely,
AndrewB
Posted by PeterJ on April 27, 2000, at 0:33:49
In reply to More Qs for PeterJ, posted by AndrewB on April 26, 2000, at 11:07:18
> 1) Are there rough equivalents to amineptine. For example, are COMT inhibitors possibly substitutes since they would result in >increased dopamine in the synaptic clefts as does amineptine. By the way, does it seem like COMT inhibitors have AD potential >either alone or in combo with an MAO-A, MAO-I or L-Dopa.
COMT inibitors may have some anidepressant potential. See the other thread on this topic.
The closest equivalents to amineptine might be stimulants such as dexedrin, ritalin, mazindol or diethylpropion. Other drugs known to effectively enhance dopamine are MAOIs (deprenyl in particular), l-dopa, direct agonists such as bromocriptine or pramipexole, presynaptic antagonists such as sulpiride and possibly other drugs such as bupropion.> 2) Can tyrosine supplementation potentiate the effect of amineptine. One person stated that tyrosine potentiated dexadrine by >preventing dopamine depletion. Amphetamines like dexadrine are D2 reuptake blockers. Amineptine has similar mechanics, being >a dopamine reuptake blocker.
I would expect tyrosine to have some potentiating effect. In animal studies, tyrosine conversion to dopamine is increased in situations of increased dopamine turnover. In human studies, delpletion of serum tyrosine has been shown to prevent the stimulant effects of amphetamine. Thus tyrosine might reduce any dopamine depletion by amineptine. The magnitude of this effect and whether or not it would prevent withdrawal symptoms is harder to estimate. Tyrosine does seem to have modest clinical benefits in some cases of depression or stimulant addiction.
> 3) Is it important to use a dopamine neuron neuroprotective agent such as pramipexole (a D2 agonist) when using agents such as >amineptine that raise dopamine levels. Pramipexole may provide its neuroprotective effects through the depression of dopamine >metabolism, antioxidant effects and the stimulation of trophic activity.
Amineptine and similar drugs are not likely to damage dopamine neurons unless taken in extremely high doses. Thus I would not be too worried about neuroprotection in the short term. There might be some logic in taking pramipexole in the long term. It may also have antidepressant properties itself.
In terms of enhancing dopamine activity and protecting dopamine neurons, the MAOI deprenyl (selegeline, eldepryl) should be mentioned. It is a standard Parkinsons treamtment due to its dopamine boosing effect. It also prevents the activation of certain toxins which may damage dopamine neurons.> 4) Is it possible for exercise to deplete dopamine and NE stores. After hard exercise, when unmedicated, I experience extreme >mental fatigue following exercise. It starts maybe 12 hours (the next morning) after the exercise and lasts for maybe three days >after that. Symptoms include loss of memory, mental confusion, busy head (increased internal dialogue, often self critical), lack of >vigilance, physical fatigue, irritability, dysphoria, feelings of vulnerability, feelings of indecision, tiredness, spots and worms >(floaters) in visual field sometimes accompanied by vertigo and mild orthostatic hypotension. It can get so bad that I’m not able to >remember my own phone number or do simple number tasks. NE and dopamine (especially D2,D3) receptor transmission >enhancers such as amisulpride and reboxetine are able to completely take away these symptoms except for the muscle soreness.
> The muscle soreness is taken away by high doses of 7-keto DHEA.Exercise may well deplete dopamine and norepinephrine. There is some laboratory evidence of this. Clincally, Dr. Birkmayer of Vienna, a leading Parkinsons expert, has observed a worsening of symptoms immediately following exercise, which he attributes to dopamine depletion.
Perturbations of the hypothalamic-pituitary-adrenal axis may also be a factor in exercise fatigue. Interestingly, serotonin may increase fatigue after exercise.
I am encouraged to hear you have gotten good results for this symptom from amisulpiride and reboxetine. I have similar symptoms myself. How would you compare the effects of amisulpiride vs. reboxetine?> 5) Does D1 receptor stimulation potentiate D2 receptor function. Does serotonin potentiate D2 receptor function. There is >apparently a complex interrelationship of potentiation and inhibition between different dopamine receptors. Also, it is thought that >part of the AD effect of serotenergic ADs is due to enhancement of D2 function.
I have an entire book in my collection called "D1 D2 Receptor Interactions." I can't summarize it all right now, but generally D1 stimulation does potentiate D2. In fact, in some cases a minimum of D1 stimulation is necessary before D2 stimulation has any effect. This does not apply to presynaptic D2 receptors which are independant of D1. I'm still trying to figure out the clinical implications of this. D1/D2 interactions may affect circadian rhythms.
> Sorry to ask so many questions. They all however are so important to me.
> Sincerely,
>AndrewBAs I am in a similar situation myself, I understand the desire to ask questions.
Peter
Posted by Scott L. Schofield on April 27, 2000, at 7:57:46
In reply to Re: More Qs for PeterJ, posted by PeterJ on April 27, 2000, at 0:33:49
Hi Andrew.
Peter's something, isn't he?
A few notes:
> > 2) Can tyrosine supplementation potentiate the effect of amineptine. One person stated that tyrosine potentiated dexadrine by preventing dopamine depletion. Amphetamines like dexadrine are D2 reuptake blockers. Amineptine has similar mechanics, being a dopamine reuptake blocker.
> I would expect tyrosine to have some potentiating effect. In animal studies, tyrosine conversion to dopamine is increased in situations of increased dopamine turnover. In human studies, delpletion of serum tyrosine has been shown to prevent the stimulant effects of amphetamine. Thus tyrosine might reduce any dopamine depletion by amineptine. The magnitude of this effect and whether or not it would prevent withdrawal symptoms is harder to estimate. Tyrosine does seem to have modest clinical benefits in some cases of depression or stimulant addiction.
To give tyrosine a good shot at doing anything in the brain, it needs to get there in the first place. Tyrosine competes with other amino acids for uptake across the blood-brain barrier. It competes with other large neutral amino acids for access to L-system carrier uptake sites. These other amino acids comprise tryptophan, phenylalanine, leucine, isoleucine, and valine. It is suggested that any of these should be ingested in the absence of all the others. Tyrosine should therefore be taken on an empty stomach or along with a meal devoid of protein. Phenylalanine may be a better choice to fill the role proposed for tyrosine "supplementation" in treating depression. It tends to cross the blood-brain barrier more easily. Once in the brain, phenylalanine is converted to tyrosine. Tyrosine is then converted to l-dopa, which is then converted to dopamine which is then converted to norepinephrine. The rate-limiting step here is the conversion of tyrosine to l-dopa by tyrosine hydroxylase. Adding large amounts of either tyrosine or phenylalanine won't have much effect on levels of catecholamine neurotransmitters if this enzyme is already saturated. L-dopa has been tried for treating depression in much the same way as has 5-hydroxytryptamine, its analogue along the metabolic route towards the synthesis of serotonin. Perhaps a therapeutic effect is exerted by tyrosine via action as a false transmitter. I don't know.
> > 4) Is it possible for exercise to deplete dopamine and NE stores.
I once had a doctor advise me to not perform any high-intensity exercise (resistance training) while trying to get well as it tended to deplete catecholamines. He said that such exertion was counterproductive towards achieving a remission of depression. Traditional cardiovascular exercise, he said, was O.K.
- Scott
Posted by AndrewB on April 27, 2000, at 12:00:30
In reply to Re: More Qs for PeterJ, posted by PeterJ on April 27, 2000, at 0:33:49
Peter,
Again thank you very much for your responses to my questions. I feel deeply appreciative for you having shared your knowledge.
You asked how amisulpride compares to reboxetine in terms of exercise induced fatigue. Amisulpride removes something like 60% of the symptoms by itself. It helps with all the symptoms except the unusual muscle soreness. It helps immensely with the brain fog, memory impairment, moodiness and irritability, phsyscial fatigue, low mood, critical self talk, attention and maintaining wakefullness. For an interesting discussion on how the D2 recpetors are involved in such symptoms go to www.prys.net/articles/bruno/runninghead.html. It is actually an article about Polioencephalitis and how its fatigue symptoms are ameliorated with bromocriptine. Polioencephalitis's fatigue symptoms closely mimic mine. For example, in general the fatigue symptoms of Polioencephalitis are triggered or exacerbated by physical overexertion or emotional stress. I can certainly relate to that. The article also notes the similarity of the Polioencephalitis symptoms with those of Chronic Fatige Syndrome and speculates that some with this disorder may be helped by
D2 activators.I've been taking amisulpride since last July. In December however, I had a partial poop out or had gained some tolerance to amisulpride. It was then I started to look for ways to bolster the amisulpride. There was also another event prior to December where I had a 10 day period of heavy physical exertion and emotional stress thatt left me tired and depressed. I realized that amisulpride by itself for me isn't always enough. Amisulpride is like a campfire; it will keep you warm except for when a strong wind (stress) kicks up. By the way, the amisulpride regianed its original power of effect when I took a 4 day holiday from it.
Reboxetine helps with fatigue symptoms by increasing general arousal which includes mental focus and energy. Because you are more aroused, you end up doing more things, getting more done, including socializing. It also combats daytime sleepiness.
I've also have added on other medicines that have removed what remains of the exercise fatigue. Anti-inflammatories (i.e. nalprexone) taken the day of the exercise take away irritability. 7-keto takes away muscle soreness. Mirapex (pramipexole) bolsters amisulpride, making it closer to being bulletproof. Amineptine I am still evaluating but it seems to take away any sluggishness that remains the day after hard exercise. I also think I may be able to surf through times of high stress by simply increasing my amineptine dosage. My current plan is to take amineptine usually only 4 or 5 times a week, taking plenty of drug holidays in order to keep it fully potentiated.
All the best,
AndrewB
Posted by Ant-Rock on April 27, 2000, at 14:45:21
In reply to Re: PeterJ, posted by AndrewB on April 27, 2000, at 12:00:30
Hi Andrew,
After reading the previous posts, I was wondering what dosage of Amineptine you are on.
Thats all for now,
Regards,
Anthony
Posted by AndrewB on April 27, 2000, at 15:05:06
In reply to Re: andrewb, posted by Ant-Rock on April 27, 2000, at 14:45:21
Anthony,
100mg. in the morning
Posted by Alfred on April 28, 2000, at 2:14:14
In reply to Re: andrewb, posted by AndrewB on April 27, 2000, at 15:05:06
I don't have a problem with depression, but after working in the garden for about 2&1/2 hours I became uncharacteristically irritable and hypercritical. Do I need to premedicate before exercise? I always assumed that exercise would cause the release of endorphins and improve mood. Also, an unrelated question, where do alpha-blockers figure into the above discussion? I heard years ago that Trazadone was thought to work because of alpha-blocking properties, I think this idea has been revised since then. Can anyone comment on possible adverse reactions of moderate to heavy exercise as it pertains to mental health in general?
Posted by PeterJ on April 28, 2000, at 2:52:00
In reply to Re: More Qs for PeterJ - Butting in., posted by Scott L. Schofield on April 27, 2000, at 7:57:46
>
> To give tyrosine a good shot at doing anything in the brain, it needs to get there in the first place.I agree. Tyrosine or phenylalanine must be taken without protein. It may be even better to take it on a completely empty stomach as the insulin release caused by food may lead to the amino acids being taken up by muscle instead of brain.
Saturation of tryosine hyroxylase is indeed rate-limiting. The enzyme is normally saturated but may not be in conditions of high dopamine turnover.
Another point to consider is that some of the actions of tyrosine or phenylalanine may be due to peripheral conversion to adrenaline or noradrenaline, either in the adrenals or in sympathetic neurons. Having taken tyrosine, phenylalanine (d- and/or l-) and l-dopa, I find that tyrosine and l-phenylalanine produced more pronounced peripheral effects (e.g. tachychardia) and a more adrenergic rather than dopaminergic feeling.
Peter
Posted by AndrewB on April 28, 2000, at 7:13:42
In reply to Exercise and MH in general., posted by Alfred on April 28, 2000, at 2:14:14
> I don't have a problem with depression, but after working in the garden for about 2&1/2 hours I became uncharacteristically irritable and hypercritical. Do I need to premedicate before exercise? I always assumed that exercise would cause the release of endorphins and improve mood. Also, an unrelated question, where do alpha-blockers figure into the above discussion? I heard years ago that Trazadone was thought to work because of alpha-blocking properties, I think this idea has been revised since then. Can anyone comment on possible adverse reactions of moderate to heavy exercise as it pertains to mental health in general?
Alfred,
For most people exercise makes them feel better. Some subpopulations feel worse however. For example, those with Chronic Fatigue Syndrome have their symptoms exacerbated by exercise. For those with depression, most by in large feel better with exercise. Their is only a small subset whose depressive symtoms are made worse by exercise.
For you, hopefully, this irritability and hypercritical mood was just a one time thing. If not, perhaps it is just sore muscles barking back at you. Then perhaps all you need is to take some ibuprofin or nalproxin.
I've read in one place that muscle tension builds up lactic acid, which can create irritable and panicky feelings associated with anxiety. Calcium neutralizes the effects of excess lactic acid, and vitamin D assures its proper absorbtion.
AndrewB
Posted by Cecilia on May 1, 2000, at 4:25:13
In reply to Exercise and MH in general., posted by Alfred on April 28, 2000, at 2:14:14
> I don't have a problem with depression, but after working in the garden for about 2&1/2 hours I became uncharacteristically irritable and hypercritical. Do I need to premedicate before exercise? I always assumed that exercise would cause the release of endorphins and improve mood. Also, an unrelated question, where do alpha-blockers figure into the above discussion? I heard years ago that Trazadone was thought to work because of alpha-blocking properties, I think this idea has been revised since then. Can anyone comment on possible adverse reactions of moderate to heavy exercise as it pertains to mental health in general?
Re increased irritability after working in the garden, were you perhaps angry because you thought another household member should have been helping you? Did you perhaps never want a house and garden in the 1st place but got talked into it by a partner? Were you forced to do garden chores as a chid and resented it? Just some thoughts.
Posted by mb888 on June 4, 2002, at 18:51:54
In reply to Re: PeterJ, posted by AndrewB on April 27, 2000, at 12:00:30
Andrew, wondering since others above have suggested Amineptine is impossible to find anymore, yet you apparently are still using it, how do you come by it?
Bill
Posted by TallPaul on August 18, 2002, at 0:57:23
In reply to Andrew and his Amineptine use, posted by mb888 on June 4, 2002, at 18:51:54
> Andrew, wondering since others above have suggested Amineptine is impossible to find anymore, yet you apparently are still using it, how do you come by it?
>
> BillBill - Did you ever get a response on where Andrew got his amineptine?
Posted by aazospiro on February 12, 2004, at 8:06:40
In reply to Re:Down-Regulation and Tolerance: Qs for PeterJ, posted by PeterJ on April 26, 2000, at 1:46:17
>
> The greatest NE and 5-HT receptor changes produced by antidepressant
> drugs appear to take place during the first few weeks of drug use, which
> is coincident in time with the initial therapeutic effect. While later
> changes can occur and might be associated with loss of antidepressant
> effect ("poop out") this is not typical. Some depressed persons do
> tend to develop tolerance in this way and thus don't respond well
> to antidepressants. (Curiously, they may also improve transiently
> during drug withdrawal.)
>
> With DA, the story is different. DA drugs tend to produce more rapid
> beneficial effect, however it has been clinically observed that loss
> of benefit with continued use is also more common. It's not inevitable
> -- many people benefit from DA drugs for years -- but it can occur.
>
> The reason for tolerance to DA drugs is complex and not fully understood.
> In the late 80s, Gold and others advocated the catecholamine depletion
> explanation. I don't think this has been conclusively disproven, but
> recent research has concentrated on receptor changes. These however
> are very complex and dependant on the exact schedule of drug
> administration.
>
> Chronic treatment of rats with stimulants may produce post-synaptic
> DA receptor sensitization (kindling) or desensitization (tolerance).
> Intermittent administration tends to sensitize while continuous
> administration tends to lead to tolerance.
>
> Another newly revealed source of tolerance to DA drugs is super-
> senisitivity of pre-synaptic DA autoreceptors (D2). These super
> sensitive receptors inhibit DA output during the drug withdrawal
> period.
>
> It's not clear why this supersensitivity develops.
>
> In the case of Amineptine, if the initial benefit is dopaminergic, then
> tolerance to that benefit is a theoretical concern. As I said, it's
> not inevitable, but if you think you are observing tolerance, then
> you may be right.
>
> Drug holidays might help, but there is no standard protocol for this.
> Some patients with narcolepsy use drug holidays, but they are usually
> pretty miserable during the "holiday". Your own observations
> may be the best guide.
>
> Intermittent use may produce sensitization. This may be good--if
> sensitization to the benefits occurs. On the other hand, sensitization
> to adverse effects of DA (irritiablity, psychosis) may also occur, which
> is not so good.
>
> If pre-synaptic DA supersensitivity is the problem, then sulpiride, which
> blocks those receptors, would be ideal. The use of amineptine +
> sulpiride ,which some have suggested on this board, makes perfect sense.
> On the other hand, if you observe withdrawal symptoms from amineptine alone,
> then withdrawal from amineptine + supliride may be a double whammy.
>
> Finally, despite my cautions about amineptine, I think it verges on a
> crime against humanity to remove it from production when there are
> at least some people who might benefit from it who have not responded
> to other drugs.
>
> Peter
Hi Peter,I have been reading your posts, and neurobiologically they make perfect sense. My question to you is this; and let me give you a little history first.
I have used all of the SSRI's and although they all made things worse. My anxiety would get worse, handshake worse, sleep problems worse. Then there was moclobemide, which was alittle better except for the irritability which was made worse. Then there was propranolol, which helped the handshake but made you feel like you had a ton of bricks on your chest. Then there was tegeretol, nasty; dysphoric, no motivation, zombie. Then depakote, the same thing only nastier. Then Lithium, whoa! double nasty. Topiramte, the same thing.
Then finally some sunshine. And this came with believe it or not 62.5 mg of Sinemet every 8 hours. I have been on it now for 3 months i sleep is good, motivated, no irritability, sex is great, my mood is wonderful especially in the morning. Have you heard of this before? Can chronic Sinemet administration cause d-2 receptors or any other subtypes to downregulate? I really need your help on this one. I amazed at my apparent recovery.
Posted by whitdaddy on November 3, 2004, at 9:14:45
In reply to Re:Down-Regulation and Tolerance: Qs for PeterJ, posted by aazospiro on February 12, 2004, at 8:06:40
I have been fighting treatment resistant depression for 14 years and have experienced tolerance and "poop-out" with every single medication that I have tried.
I have been told that I am part of a rare percentage of the population that has a highly sensitive neuro-protective system. What I am wondering is what biological actions are responsible for this. Does it have something to do with my liver producing enzymes to eliminate what it perceives as a threat? Is it simply the neurons in my brain adjusting levels of receptor and/or reuptake sites?
Whatever you think the problem might be, is there anything I can do to "trick" my body into accepting medications? Any and all information by anyone is much appreciated.
Thanks,
whitdaddy
Posted by denise1904 on November 19, 2004, at 11:02:12
In reply to Down-Regulation and Tolerance: Question, posted by whitdaddy on November 3, 2004, at 9:14:45
Hi,
I'd be really interested to kow if anyone has any views, theories or ideas regarding the previous message?
Denise
Posted by Dave001 on November 22, 2004, at 16:12:42
In reply to Down-Regulation and Tolerance: Question, posted by whitdaddy on November 3, 2004, at 9:14:45
> I have been fighting treatment resistant depression for 14 years and have experienced tolerance and "poop-out" with every single medication that I have tried.
>
> I have been told that I am part of a rare percentage of the population that has a highly sensitive neuro-protective system. What I amI think "highly efficient nervous system" might be a better way of saying the same thing; but that's just me...
> wondering is what biological actions are responsible for this. Does it have something to do with my liver producing enzymes to eliminate what it perceives as a threat? Is it simply the neurons in my brain adjusting levels of receptor and/or reuptake sites?The precise mechanisms are complicated and no doubt variable depending upon the drug. It is doubtful that liver enzyme induction is the problem, though, since this is much easier to measure and doesn't seem to happen much with most drugs we use in depression and related conditions.
> Whatever you think the problem might be, is there anything I can do to "trick" my body into accepting medications? Any and all information by anyone is much appreciated.
>Maybe. Who knows? The most obvious approach would be to try cycling between different medications. When a given medication or combination stops working, switch to another which has worked for you in the past.
This is the end of the thread.
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