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
poster:PeterJ
thread:30864
URL: http://www.dr-bob.org/babble/20000420/msgs/31309.html