Posted by undopaminergic on April 20, 2008, at 19:26:55
In reply to Re: Husbands Suggestion of Nardil for me, posted by SLS on April 19, 2008, at 5:25:39
> > > Hi Racer.
> > >
> > > IMHO, Nardil is the second most efficacious drug on the planet. Clorgyline is the first. Both of these drugs are potent inhibitors of MAO-A.
> > >
> >
> > I read an article today concluding that trimipramine wss more effective than MAOIs (phenelzine and isocarboxazid) in most cases.
>
> Nope. I hope you take into consideration more than one article to conclude for yourself what was indicated by the authors of that paper.
>Quote: "The results show a clear superiority for the tricyclic antidepressant trimipramine over MAOIs and the combination of trimipramine plus MAOIs in this large but unselected group of depressed outpatients, most of whom also received diazepam."
There were limitations of this particular study. They used a maximum of 60 mg of phenelzine and little more than 30 mg isocarboxazid, which may have been insufficient, and furthermore, the duration of the trial was only 6 weeks, which may also have been insufficient. Nevertheless, it illustrates the reasons why MAOIs are not first-line agents.
>
> > Targeting MAO-A makes sense if you're more interested in boosting serotonin and noradrenaline. For extracellular dopamine, it is more logical to target MAO-B (and COMT, in theory), with MAO-A as a secondary target. Inhibition of intracellular MAO-A (*) is associated with downregulation of tyrosine hydroxylase activity, which to a considerable extent defeats the effects of MAO inhibition. (* there is very little intracellular MAO-B.)
>
> By the way, there is a significant amount of DA that acts as a substrate for MAO-A. It is regionally selective, though. I think some is located at levels higher than the basal ganglia.
>There are differences betwen regions and between species. The details are complex, but as an example, clorgyline at a MAO-A selective dose, reduces DA metabolites in the rat nucleus accumbens (NAc), but fails to alter basal extracellular DA levels or cocaine-induced increases thereof. Selegiline, on the other hand, at MAO-B selective doses, doesn't reduce metabolites, but clearly potentiates the effects of cocaine on extracellular DA. This illustrates 1) the dominant role of MAO-A in DA metabolism in the rat NAc under normal conditions, 2) the downregulation of DA synthesis (no change in DA levels, despite reduced metabolism) in response to MAO-A inhbition, and 3) the role of MAO-B in extracellular DA metabolism under conditions of elevated DA concentration (as produced by reuptake inhibition by cocaine).
MAO-B is of much greater significance in primates than in rats. Nevertheless, chronic selegiline treatment actually attenuates the subjective effects of cocaine in humans. This may reflect desensitation of DA receptors following prolonged elevation of extracellular DA levels by selegiline treatment.
> The only truly effective MAOIs are potent inhibitors of MAO-A. Of this I am certain.
>All known potent MAOIs are capable of potent inhibition of MAO-A, depending on dose. However, I see no reason for choosing a MAOI that preferentially inhibits MAO-A and hence introduces the risk of cheese reaction and serotonin syndrome even at subtherapeutic doses, while provoking downregulation of neurotransmitter synthesis on top of it. Why not start with a noradrenaline+dopamine reuptake inhibitor (e.g. methylphenidate) that blocks (or slows) tyramine uptake into sympathetic nerve terminals and produces an elevation of synaptic concentrations of these neurotransmitters without any enzyme inhibition at all, and then introduce a MAO-B-preferring inhibitor at increasing doses until the desired effect is achieved? In most treatment-resistant cases, a considerable degree of MAO-A inhibition will be required in addition to the catecholamine reuptake blockade and the near-total MAO-B inhibition. Another potential advantage of this protocol is the likely alleviation of MAOI-induced hypotension.
poster:undopaminergic
thread:823803
URL: http://www.dr-bob.org/babble/20080420/msgs/824471.html