JohnBoy2000
Bluelighter
- Joined
- May 11, 2016
- Messages
- 2,465
A clinical director, who also had a masters in neuroscience, was trying to explain to me one time that, due to what yields the effects of anti-depressants, the downstream biological implications and variations, that occur passed the post synaptic membrane located receptors binding with the neurotransmitter - that it's not a good idea to base the potential effectiveness of a drug, on it's pharmacodynamic binding profile.
Point being - by example, SSRI's.
Apparently, their only differentiating characteristics, are - their secondary characteristics.
Prozac - 5HT2c blockade.
Setraline - slight DRI
Paroxetine - slight mACh blockade
etc.
But - primarily - they all act as SRI's
And, pertaining to that - their SRI action - is all the same - is it not??
That is to say, if we took away their secondary characteristics, they'd all be the same drug, with the same effect - no?
Overlooking there their potency relative to SR inhibition - but you get the idea.
So - now - let's examine noradrenergic or norepinephrine RI's - hmm?
Desipramine
Nortriptyline
Maprotiline
and..... Reboxetine.
The former three - they hit lots of receptors, in addition to the noradrenergic transporter - right?
Cholinergic blockade, pretty prominent with many.
Alpha 1 adrenergic blockade.
Certain 5HT receptor subtypes are blocked.
Certain amount of 5HT transporters, are also blocked
etc
You get the idea.
The former three - have shining clinical trial records.
They are effective anti-depressants, no doubt about it.
Then we have - the black sheep.
Reboxetine.
Highly selective for the noradrenergic transporter.
So many reports circulate that - it's just no good. It don't work.
And clinical trial meta-analysis reflects that, response and remission rates, in contrast to the likes of the former three - reboxetine just performs worse.
But here's the thing.
The primary characteristic of all three drugs - is, in short, increasing the amount of noradrenaline/norepinephrine, neurotransmitter - in the synapse - mmkay?
Therefore - that transmitter binds with the post-synaptic receptor, which activates 2nd messengers etc - initiates the post-synaptic transduction cascade - yielding the anti-depressant effect; correct?
For say, desipramine, vs reboxetine - in terms of blocking the reuptake transporter - when this is done for each drug - does the means by which it blocks said transporter - does it result in some kind of alteration in the nature of noradrenergic neurotransmitter that is accumulated in the synapse - and therefore result in some kind of variation is the resulting post-synaptic biological cascade?
Cause if that were the case - that would be a very clear explanation as to the variation in the efficacies of each drug?
Microdialysis examinations demonstrate that - Reboxetine - it is highly selective, and highly effective, for blocking the noradrenergic transporter.
There is no question that, it increases synaptic noradrenaline levels.
As is the case for desipramine, and the other NRI's.
Then - why oh why - is there the efficacy differential??
I mean - logically, the only conclusion is that, it's the secondary characteristics - the, generally speaking, unwanted characteristics, of older less selective tricyclics, that are exerting the anti-depressant effect.
On paper - that's the only explanation - right?
You see the paradox?
Point being - by example, SSRI's.
Apparently, their only differentiating characteristics, are - their secondary characteristics.
Prozac - 5HT2c blockade.
Setraline - slight DRI
Paroxetine - slight mACh blockade
etc.
But - primarily - they all act as SRI's
And, pertaining to that - their SRI action - is all the same - is it not??
That is to say, if we took away their secondary characteristics, they'd all be the same drug, with the same effect - no?
Overlooking there their potency relative to SR inhibition - but you get the idea.
So - now - let's examine noradrenergic or norepinephrine RI's - hmm?
Desipramine
Nortriptyline
Maprotiline
and..... Reboxetine.
The former three - they hit lots of receptors, in addition to the noradrenergic transporter - right?
Cholinergic blockade, pretty prominent with many.
Alpha 1 adrenergic blockade.
Certain 5HT receptor subtypes are blocked.
Certain amount of 5HT transporters, are also blocked
etc
You get the idea.
The former three - have shining clinical trial records.
They are effective anti-depressants, no doubt about it.
Then we have - the black sheep.
Reboxetine.
Highly selective for the noradrenergic transporter.
So many reports circulate that - it's just no good. It don't work.
And clinical trial meta-analysis reflects that, response and remission rates, in contrast to the likes of the former three - reboxetine just performs worse.
But here's the thing.
The primary characteristic of all three drugs - is, in short, increasing the amount of noradrenaline/norepinephrine, neurotransmitter - in the synapse - mmkay?
Therefore - that transmitter binds with the post-synaptic receptor, which activates 2nd messengers etc - initiates the post-synaptic transduction cascade - yielding the anti-depressant effect; correct?
For say, desipramine, vs reboxetine - in terms of blocking the reuptake transporter - when this is done for each drug - does the means by which it blocks said transporter - does it result in some kind of alteration in the nature of noradrenergic neurotransmitter that is accumulated in the synapse - and therefore result in some kind of variation is the resulting post-synaptic biological cascade?
Cause if that were the case - that would be a very clear explanation as to the variation in the efficacies of each drug?
Microdialysis examinations demonstrate that - Reboxetine - it is highly selective, and highly effective, for blocking the noradrenergic transporter.
There is no question that, it increases synaptic noradrenaline levels.
As is the case for desipramine, and the other NRI's.
Then - why oh why - is there the efficacy differential??
I mean - logically, the only conclusion is that, it's the secondary characteristics - the, generally speaking, unwanted characteristics, of older less selective tricyclics, that are exerting the anti-depressant effect.
On paper - that's the only explanation - right?
You see the paradox?
