Posted by Elizabeth on June 30, 2001, at 1:29:53
In reply to Re: MAOIs, benzos, etc. » Elizabeth, posted by paulk on June 29, 2001, at 19:29:43
> I was told it takes about three weeks to knock out enough MAO to raise the level of monoamines.
Huh. This must be the same as the spiel pdocs give their overly-curious SSRI patients about how the reason it takes the drugs so long is because you have to "build up therapeutic levels in your blood." (In fact, transporter blockade -- and resulting increases in extracellular serotonin -- occurs within hours of the first dose. This is why a single dose causes side effects but no therapeutic effect. < sigh > :-) )
> Sort of what my doctor just told me yesterday – the drug is so cheap – and there doesn’t seem to be a problem with knocking out too much of the MAO so why not just keep the dose up for an incremental improvement.
Yeah. You're not going to be able to maintain adequate MAO inhibition if you drop down to an ineffective dose.
> >I don't know of any evidence supporting the idea that a lower maintenance dose is clinically effective. A dose of around 45 mg/day typically results in 80% inhibition of MAO, incidentally.
>
> That’s not enough from what I understand.80% is a standard number that's tossed around a lot, although the truth is probably that the therapeutic level is not exactly the same for every individual. (45 mg isn't usually a high enough dose, anyway.)
> >MAO begins to return to normal levels within a few days;
>
> Yes, but getting down to 90% can take much longer – 80% probably is not enough to do any good.The point (whether or not it's 80 or 90%; estimates vary) is, when you have 80% (or 90%) inhibition, and then you cut the dose of the inhibitor by 75%, the MAO is going to start returning. You're not going to be able to maintain that level of enzyme inhibition on the reduced dose.
> Think of a flooded basement up to the first floor with water still coming in through the walls – you turn on a small pump that has to pump out the basement AND any water that is still coming in.
No thanks. I hate metaphors and analogies. :-) (Seriously, there's a reason I don't like argument by analogy -- the analogy could have a major flaw.)
> The monoamines only start to increase after the MAOs are down to about 90%. This explains the slow onset of the drug – especially when you realize that the monoamines need to be higher for another 3 – 6 weeks for the drug to reach maximum effectiveness.
MAOIs, work faster than other ADs, if anything. It doesn't take weeks for neurotransmitter levels to increase; that happens early, as with the reuptake inhibitors. MAO is the major pathway for removal of extraneous extracellular monoamines; other enzymes like the methyltransferases are relatively minor, and even the monoamine transporter pumps do not play as great a role as MAO. There may be some time delay in percent inhibition, but it isn't going to play a major role in the onset of action, which is due to the effects of chronic increase in neurotransmitter levels.
> I sort of though so – I asked about that and my doc said it had more to do with lawyers – in theory you should be able to switch between MAOIs without waiting
In theory. There have actually been cases which resembled what is now known as serotonin syndrome. Interestingly (perhaps), they all seemed to occur when the switch was between tranylcypromine and phenelzine or isocarboxazid (i.e., a non-hydrazine and a hydrazine).
> – probably the attitude is that it would cost a lot to study – so they go ultra conservative and reduce risk of a lawsuit and reserve an extra excuse.
Precisely! < g >
> Not to mention the liability costs of doing so. If it weren’t for all the lawsuits, I bet it would have been rewritten already.
I wonder if we can sue them for not rewriting it? < chuckle >
> I would have to see numbers on this – the body is replaces MAO constantly – but sort of slowly – to reach a steady state of 90% is supposed to take weeks.
It's rather complicated, but the long and short of it is that antidepressant effects don't result (directly) from increased NT levels, but from long-term (several weeks) effects of increased NT levels. (At least, that's the current understanding. < g >)
> The tertiary effect of the increase in neuro-transmitters is immediate AND long term – I respond in a better mood quite rapidly to SSRIs.
That's not the usual time course of recovery on any drug currently labelled for depression.
> I have looked for this GABA effect written somewhere – where did you see it? (not in the PDR of course)
Textbooks, articles...I don't know where I first read of it. Try Medline?
> > (BTW, in case this is of any relevance, I have primary depression, while the panic may be primary or it may result from the depression and other factors. It's definitely not the case that my depression is the result of panic disorder, because I was depressed long before I ever had a panic attack.)
>
> Atypical depression?No. "Major depressive disorder with melancholic features" and "panic disorder without agoraphobia." (IOW, tricyclics would be indicated if I could tolerate the bloody things. < g >) I should add that the depression was early-onset (around age 10, unusual for melancholia) and that I have a mixed family history of typical and atypical depressions (the latter also sometimes being associated with panic disorder, alcoholism, and/or migraine). This makes everything terribly complicated, and it's one of the reasons I think I will end up needing a combination of medications (perhaps MAOI + TCA).
> I’m confused – if we inhibit GABA transaminase – wouldn’t there be an increse in GABA?
Exactly! And that's what Nardil does. (I'm not sure about Marplan, though.)
> I’m Confused again – I would think that an increase in NE would cause an increase in BP – as happens with Effexor????
You'd think that, wouldn't you? NE has different effects at different receptor subtypes. For example, the antihypertensive drug clonidine is an alpha2-adrenergic autoreceptor agonist (Remeron is an alpha2 antagonist). I'm not sure what the details are in the case of MAOIs; it's not that they decrease blood pressure, but rather, they decrease the autonomic response to change in posture, resulting in lowered blood pressure upon rising.
Explanations for the side effects of these drugs are often as woefully lacking as the explanations for their therapeutic effects.
> Yes – but he loved his manic state – couldn’t work or anything, but seemed not to get psychotic or nasty at the top – just outrageous and uninhibited -
That's bad enough, believe me.
> Yep – that’s me. Even the very small dose of Clonazepam sure helps dampen the reactivity – just enough to keep me from moving from appropriately angry to feeling threatened and escalating the conflict.
I've encountered this kind of mood-reactivity associated with atypical depression before. It interests me a great deal. I'm just glad to hear you've found relief.
-elizabeth
poster:Elizabeth
thread:65795
URL: http://www.dr-bob.org/babble/20010625/msgs/68444.html