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Re:Down-Regulation and Tolerance: Qs for PeterJ

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.


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URL: http://www.dr-bob.org/babble/20040210/msgs/312366.html