• N&PD Moderators: Skorpio | thegreenhand

Clomipramine | The "Gold Standard" when it comes to Depression and OCD?

Holgerr

Greenlighter
Joined
Mar 7, 2018
Messages
15
I've been reading the following articles:
https://psychotropical.info/clomipramine-potent-snri-anti-depressant/
https://psychotropical.info/tca-intro/
https://psychotropical.info/snri-intro/

Seems to be a pretty potent drug: SNRI, antagonist of the alpha1-adrenergic receptor, the histamine H1 receptor, the serotonin 5-HT2A, 5-HT2C receptors, the dopamine D1, D2, and D3 receptors, and the muscarinic acetylcholine receptors. It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system; so that speaks for itself.

The reviews on drugs.com and other sites also are quite positive.

The following ranking is interesting: http://slatestarcodex.com/2015/04/30/prescriptions-paradoxes-and-perversities/

These numbers are based on aggregated patient ratings. Top 4 drugs:
# Nardil 1.25
# Parnate 1.23
# Chlomipramine 1.22
# Emsam/selegeline 1.07

=> Clomipramine roughly on pair with MAOI, followed by Nefazodone (R.I.P) and Imipramine. Imipramine is also a potent SNRI, but lacks the strong 5HT-antagonism compared to Clomipramine. I suppose that's the pharmacological difference which makes Clomipramine superior... ?

Clomipramine exhibits some antagonism of dopamine D1, D2 and D3 receptors... can one expect some clinical & therapeutic benefits from this?

Clomipramine acts as a functional (potent!) inhibitor of acid sphingomyelinase (FIASMA): http://en.wikipedia.org/wiki/FIASMA
Some interesting graphs regarding antidepressant FIASMAs: http://d-nb.info/1011278227/34

Who here has been on Clomipramine and what were your experiences with it?
 
It makes you wonder why tranylcypromine and phenelzine are nowhere near as popular antidepressants as fluoxetine or paroxetine. What this ranking does not take into consideration is that different drugs are prescribed in different situations and different drugs are reviewed by different patients suffering from different conditions, you know nothing about them including other drugs they may have taken. Such reviews don't really give you much information about efficacy and side effects of drugs, you have no information about people taking the drugs, you have no control groups.

Clomipramine is a tricyclic antidepressant and is a very unselective drug targeting many receptors which have nothing to do with its antidepressant properties which mainly come from serotonin reuptake inhibition, hence it's more likely to cause side effects. The usual course of pharmacological treatment for depression is that first a patient is prescribed a new generation antidepressant (SSRI's, SNRI's, NRI's etc.) with much higher selectivity for serotonin and/or noradrenaline transporters, higher therapeutic index, and less probability of causing side effects. If that treatment fails, another SSRI or SNRI may be tried, then another one. If depression is resistant to S(N)RI treatment, then MAOI's or tricyclic antidepressants are tried and in some cases they do turn out to be more effective but that doesn't make them superior as antidepressants even if you leave nasty adverse effects aside. Clomipramine is on the WHO's list mainly because it's cheap to produce, the list includes drugs that are the most cost effective.
 
It makes you wonder why tranylcypromine and phenelzine are nowhere near as popular antidepressants as fluoxetine or paroxetine.

Is that a rethorical question? Because Tranylcypromine and Phenelzine are non-selective and irreversible MAOIs. Tremendous therapeutic potential, but way more risky than an SSRI.

What this ranking does not take into consideration is that different drugs are prescribed in different situations and different drugs are reviewed by different patients suffering from different conditions, you know nothing about them including other drugs they may have taken. Such reviews don't really give you much information about efficacy and side effects of drugs, you have no information about people taking the drugs, you have no control groups.

Very true. I would argue that the people who write reviews on drugs.com often tend to be those who are actually suffering from chronic treatment-resistant depression and are constantly looking for a more effective remedy; I don't think many of their users are people who are fine with just some Lexapro.

Clomipramine is a tricyclic antidepressant and is a very unselective drug targeting many receptors which have nothing to do with its antidepressant properties which mainly come from serotonin reuptake inhibition, hence it's more likely to cause side effects. The usual course of pharmacological treatment for depression is that first a patient is prescribed a new generation antidepressant (SSRI's, SNRI's, NRI's etc.) with much higher selectivity for serotonin and/or noradrenaline transporters, higher therapeutic index, and less probability of causing side effects. If that treatment fails, another SSRI or SNRI may be tried, then another one. If depression is resistant to S(N)RI treatment, then MAOI's or tricyclic antidepressants are tried and in some cases they do turn out to be more effective but that doesn't make them superior as antidepressants even if you leave nasty adverse effects aside.

There is a certain irony here, of course:
"Ugh, tricyclics! Low selectivity for the serotonin transporter over the noradrenaline transporter, and what's with all the antagonism at histamine and 5HT2A receptors? Thankfully this is the 90's, and we have Selective Serotonin Reuptake Inhibitors!"
"...eh, maybe you do need a bit of a noradrenaline boost on top. Thankfully this is 2000, and we have SNRI's!"
"...and maybe it would be nice to have some histamine/5HT2A-antagonism-mediated anti-anxiety action, too. It's 2010, try some Seroquel on top of your antidepressant!"
"...or just have a tricyclic."

That is not to say that tricyclics are wonder drugs - many people did find them excessively sedating, and combining an SNRI with an atypical antipsychotic allows a greater degree of pharmacological fine-tuning than a single tricyclic.
Many tricyclics also had pretty significant anticholinergic effects, which would make them very unpleasant at higher therapeutic doses, and potentially much more dangerous if a significant overdose was ingested (for many patients who just require a sedating antidepressant, trazodone might be a better option).

All in all, tricyclics obviously still have their place in a psychiatrist's arsenal, but they're neither the end-all-be-all holy grail of antidepressants, nor the ideal first-line treatment.
 
Is that a rethorical question? Because Tranylcypromine and Phenelzine are non-selective and irreversible MAOIs. Tremendous therapeutic potential, but way more risky than an SSRI.
Yeahh, non-selective irreversible MAOI are the most potent stuff out there (but need diet and have many drug-drug interactions). Nonetheless useful stuff when you have treatment resistent depression.

There is a certain irony here, of course:
"Ugh, tricyclics! Low selectivity for the serotonin transporter over the noradrenaline transporter, and what's with all the antagonism at histamine and 5HT2A receptors? Thankfully this is the 90's, and we have Selective Serotonin Reuptake Inhibitors!"
"...eh, maybe you do need a bit of a noradrenaline boost on top. Thankfully this is 2000, and we have SNRI's!"
"...and maybe it would be nice to have some histamine/5HT2A-antagonism-mediated anti-anxiety action, too. It's 2010, try some Seroquel on top of your antidepressant!"
"...or just have a tricyclic."
=D

That is not to say that tricyclics are wonder drugs - many people did find them excessively sedating, and combining an SNRI with an atypical antipsychotic allows a greater degree of pharmacological fine-tuning than a single tricyclic. Many tricyclics also had pretty significant anticholinergic effects, which would make them very unpleasant at higher therapeutic doses, and potentially much more dangerous if a significant overdose was ingested (for many patients who just require a sedating antidepressant, trazodone might be a better option).
There are people, who have less side effects on tricyclics than with SSRIs.
And not all tricyclics are equally toxic.

Clomipramine isn't that sedating. It has moderate H1- and 5HT Antagonism, but is also a potent NRI. Amitrirptyline is sedating ^^

Also not everyone wants to take antipsychotics...

All in all, tricyclics obviously still have their place in a psychiatrist's arsenal, but they're neither the end-all-be-all holy grail of antidepressants, nor the ideal first-line treatment.
True that.
 
Is that a rethorical question? Because Tranylcypromine and Phenelzine are non-selective and irreversible MAOIs. Tremendous therapeutic potential, but way more risky than an SSRI.

Yes, it was, perhaps even a bit sarcastic. I later read the text below the ranking on the linked site and some valid points are made there, but still, the ranking alone presents something quite complex as something much simpler than it is.

Just to be clear I'm not advocating SSRI's or any other antidepressants in particular as superior either. It's just that you can't really pick the top antidepressant, even if MAOI's show somewhat better results for refractory depression than any other random antidepressant, it doesn't make them superior because as you wrote they are more risky. The usual course of treatment should take into account both the potential benefits and risks for a patient, hence SSRI's are more commonly used as they have much lower tendency to cause side effects and if they do cause them, they are less dangerous, at the same time they do seem to work for many people, so why put them on something much more dangerous first?

As for tricyclics, sedation is definitely not the worst downside to them, sometimes sedation may even be desired. Main risks are potential liver failure, extrapyramidal effects, and interactions with a lot of medicines due to low selectivity. Even though clomipramine is not the worst offender in this class, it's hard to consider it a gold standard.
 
even if MAOI's show somewhat better results for refractory depression than any other random antidepressant, it doesn't make them superior because as you wrote they are more risky.
You want complete remission and not a semi-remission.
Full remission of illness is the goal.


Main risks are potential liver failure, extrapyramidal effects, and interactions with a lot of medicines due to low selectivity.
How big are the risks?

With SSRIs risks are: internal bleeding and increased internal bleeding time caused by depletion of platelet 5-HT, hyponatremia, dangerous interactions caused by CYP450 inhibition (Fluoxetine, Fluxovamine and partially Paroxetine).

EDIT:
https://www.fda.gov/Drugs/DrugSafety/ucm297391.htm
https://www.fda.gov/Drugs/ResourcesForYou/SpecialFeatures/ucm297764.htm
https://www.fda.gov/Drugs/DrugSafety/ucm269086.htm
 
You want complete remission and not a semi-remission.
Full remission of illness is the goal.

If it's possible with the current state-of-the-art in medicine, then obviously yes, but what does this have to do with the argument whether clomipramine is better or not than most antidepressants? People suffering from depression do get full remission from different antidepressants and different antidepressants fail them too.

How big are the risks?

With SSRIs risks are: internal bleeding and increased internal bleeding time caused by depletion of platelet 5-HT, hyponatremia, dangerous interactions caused by CYP450 inhibition (Fluoxetine, Fluxovamine and partially Paroxetine).

EDIT:
https://www.fda.gov/Drugs/DrugSafety/ucm297391.htm
https://www.fda.gov/Drugs/ResourcesF.../ucm297764.htm
https://www.fda.gov/Drugs/DrugSafety/ucm269086.htm]

Relative to newer generation antidepressants like SSRI's and SNRI's? I don't have a ready answer for you to give you some numbers to compare, pharmacology is not my field of expertise and unfortunately I have too little spare time now to dive into recent papers on antidepressant pharmacology to give this topic justice. Basically the easiest way to get the big picture would be to dig up some review articles on specific groups of antidepressants and reviews comparing different classes of antidepressants. Certainly all antidepressants carry some risks, some may not be evident right away despite extensive research and we find out about them much later. That's how it's been with many different classes of drugs. But really, in a simplified example: the mere fact that drug A is more selective towards desired target than drug B makes drug A more desirable as the treatment because higher selectivity makes drug A safer and less likely to cause adverse effects or interactions with other drugs (metabolic pathways are another thing to consider, but I wanted to make it a simple theoretical example). There is a good reason why scientists try to design more and more selective drugs. One really can't insist on tricyclics being great considering they act on so many receptors often eliciting opposite effects.

Tricyclic Antidepressants, QT Interval Prolongation, and Torsade de Pointes]
ECG abnormalities in tricyclic antidepressant ingestion
Cardiovascular Considerations in Antidepressant Therapy: An Evidence-Based Review

The consensus is not really that SSRI's are great either, the consensus is they have the highest safety margin which along with their level of efficacy makes them first-line choice. That's how drug choices for treatment are made in other areas of medicine as well. Look at this example: you have codeine which is a weak opioid, a prodrug really, and is 10 times less potent than morphine, and you have morphine or oxycodone which are both around 10 times as strong as codeine. And you have a patient with a pretty bad toothache. What don't you give them oxycodone instead of codeine/APAP?

Another thing to keep in mind is that SSRI's are drugs that are mostly structurally unrelated and at best share some common motifs like the distance and spatial relationship between the amine and aromatic moiety which is necessary for SERT binding, so while they are much more selective for SERT than TCA's, they also differ one from another with respect to secondary effects.
 
IBut really, in a simplified example: the mere fact that drug A is more selective towards desired target than drug B makes drug A more desirable as the treatment because higher selectivity makes drug A safer and less likely to cause adverse effects or interactions with other drugs
But is there only one desired target? (=SRI?)
Let's take Clomipramine for example: Are the following targets undesired: NRI, antagonism of the alpha1-adrenergic receptor, the histamine H1 receptor, the serotonin 5-HT2A, 5-HT2C receptors... ? :?

I concur that strong antagonism of muscarinic receptors (mACh) is undesired, but what about the other stuff?


There is a good reason why scientists try to design more and more selective drugs. One really can't insist on tricyclics being great considering they act on so many receptors often eliciting opposite effects.
Are those very new drugs effective?
 
But is there only one desired target? (=SRI?)
Let's take Clomipramine for example: Are the following targets undesired: NRI, antagonism of the alpha1-adrenergic receptor, the histamine H1 receptor, the serotonin 5-HT2A, 5-HT2C receptors... ? :?

I concur that strong antagonism of muscarinic receptors (mACh) is undesired, but what about the other stuff

Antagonism at 5HT2A/5HT2C, H1 and alpha-adrenergic receptors is often associated with sedation and significant weight gain, so yes, for many patients they are, in fact, undesirable. Noradrenaline reuptake inhibition can also cause a number of rather unpleasant symptoms.

Pharmacologically, a tricyclic is essentially an SNRI and an atypical antipsychotic rolled into one. Plenty of people achieve full remission on just an SSRI, or they find that the benefits of adding noradrenaline reuptake inhibition or 5HT/Histamine/adrenergic antagonism don't outweigh the drawbacks.
 
Holgerr said:
But is there only one desired target? (=SRI?)
Let's take Clomipramine for example: Are the following targets undesired: NRI, antagonism of the alpha1-adrenergic receptor, the histamine H1 receptor, the serotonin 5-HT2A, 5-HT2C receptors... ?

Basically antidepressants aim at increasing levels of monoamines, but they don't necessarily do that via blocking monoamine reuptakes or monoamine oxidases. 5-HT2C antagonism causes an increase in dopamine in many areas of the brain such as prefrontal cortex, nucleus accumbens, and hypothalamus. Mirtazapine is an antidepressant that has insignificant effect on SERT and NET, and is mostly a 5-HT2A/2C antagonist and an antihistamine.

In case of TCA's the risk is due to the multitude of receptors that are affected and opposite effects are often elicited. Alpha-1 antagonism causes vasodilation, decreased heart rate, and sedation. Anticholinergic action basically inhibits parasympathetic nervous system and can cause increased heart rate, confusion, memory impairment, even delirium when someone is oversensitive to a drug. They are also sodium and calcium channel inhibitors which adds to the risk of cardiovascular problems associated with their use.

Holgerr said:
Are those very new drugs effective?

If you mean antidepressants, the newest ones don't have higher efficacy than those that have been around for some time now, they perform against placebo similarly to older ones. The main aim for new antidepressants is to improve the safety profile and decrease side effects, like sexual dysfunction for example, that often make people stop taking the drug even if it's helping in some way. Antidepressants can take up to several weeks before they start working, for SSRI's one theory is that this is because the initial increase in serotonin binds to 5-HT1A autoreceptors and this in turn gives negative feedback for serotonin release, once 5-HT1A autoreceptors become desensitized, serotonin release is no longer inhibited and the antidepressant effect kicks in. So a recent trend in the antidepressant industry has been to design SRI's with 5-HT1A agonistic or partial agonistic properties, such drugs are meant to desentisize 5-HT1A receptors faster and shorten the delay of antidepressant effects. Examples that ended up on the market are vilazodone and vortioxetine, but there isn't really any research that proved these drugs were generally faster-acting than other antidepressants. All in all, they are just two more drugs to choose from.
 
If you mean antidepressants, the newest ones don't have higher efficacy than those that have been around for some time now, they perform against placebo similarly to older ones. The main aim for new antidepressants is to improve the safety profile and decrease side effects, like sexual dysfunction for example, that often make people stop taking the drug even if it's helping in some way. Antidepressants can take up to several weeks before they start working, for SSRI's one theory is that this is because the initial increase in serotonin binds to 5-HT1A autoreceptors and this in turn gives negative feedback for serotonin release, once 5-HT1A autoreceptors become desensitized, serotonin release is no longer inhibited and the antidepressant effect kicks in. So a recent trend in the antidepressant industry has been to design SRI's with 5-HT1A agonistic or partial agonistic properties, such drugs are meant to desentisize 5-HT1A receptors faster and shorten the delay of antidepressant effects. Examples that ended up on the market are vilazodone and vortioxetine, but there isn't really any research that proved these drugs were generally faster-acting than other antidepressants. All in all, they are just two more drugs to choose from.

I am not sure if SSRIs are a good example for that =D
 
Antagonism at 5HT2A/5HT2C, H1 and alpha-adrenergic receptors is often associated with sedation and significant weight gain, so yes, for many patients they are, in fact, undesirable.
I rather like antagonism at 5HT2A/5HT2C, H1, because it gives me a good sleep & appetite and makes me more motivated and less apathetic / anhedonic.

Noradrenaline reuptake inhibition can also cause a number of rather unpleasant symptoms.
It can, but it also can help with indifference, anhedonia, apathy, numbness...

Pharmacologically, a tricyclic is essentially an SNRI and an atypical antipsychotic rolled into one. Plenty of people achieve full remission on just an SSRI, or they find that the benefits of adding noradrenaline reuptake inhibition or 5HT/Histamine/adrenergic antagonism don't outweigh the drawbacks.
Depends on how you measure "full remission". The recent Lancet meta-analysis didn't take "global functioning" into account, so it's doubtful how much one can rely on the results...

The question of inter-rater reliability is not even mentioned any more (9).

Cipriani et al. specifically state ?we were not able to quantify some outcomes, such as global functioning?.

I do not intend to sound scathing, but not assessing anergia or functioning more fully, is like not asking a patient with anaemia how many stairs they can manage without stopping to regain their breath, or if they are back at work etc. Such omissions indicate poor clinical assessment skills.

And, the very use of the word antidepressant is a misrepresentation. You would not call a drug an antibiotic if it only slightly slowed down the growth of bacteria, without killing them. To label drugs as antidepressants when many of them merely produce a small change in symptoms, which are not even central to what we presume is the core of the illness, is an assumptive misconception and misrepresentation.

source: https://psychotropical.info/lancet-21-antidepressants-meta-analysis/
 
I rather like antagonism at 5HT2A/5HT2C, H1, because it gives me a good sleep & appetite and makes me more motivated and less apathetic / anhedonic.


It can, but it also can help with indifference, anhedonia, apathy, numbness...


Depends on how you measure "full remission". The recent Lancet meta-analysis didn't take "global functioning" into account, so it's doubtful how much one can rely on the results...
I am starting with Clomipramine :)
 
That's the best shit I've ever been on. Works quite nicely.

Side effects are pretty harsh at the beginning of the therapy, but fade away after a while...
 
Last edited:
I'm just going to shout out for tranylcypromine and phenelzine. They were wonderful, compared to all the other crap I tried over the years. Unfortunately GPs and specialists in the UK are far too paranoid of the (frankly, comparatively modest compared to suicide) risks to prescribe them much anymore :(
 
I've been reading the following articles:
https://psychotropical.info/clomipramine-potent-snri-anti-depressant/
https://psychotropical.info/tca-intro/
https://psychotropical.info/snri-intro/

Seems to be a pretty potent drug: SNRI, antagonist of the alpha1-adrenergic receptor, the histamine H1 receptor, the serotonin 5-HT2A, 5-HT2C receptors, the dopamine D1, D2, and D3 receptors, and the muscarinic acetylcholine receptors. It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system; so that speaks for itself.

The reviews on drugs.com and other sites also are quite positive.

The following ranking is interesting: http://slatestarcodex.com/2015/04/30/prescriptions-paradoxes-and-perversities/

These numbers are based on aggregated patient ratings. Top 4 drugs:
# Nardil 1.25
# Parnate 1.23
# Chlomipramine 1.22
# Emsam/selegeline 1.07

=> Clomipramine roughly on pair with MAOI, followed by Nefazodone (R.I.P) and Imipramine. Imipramine is also a potent SNRI, but lacks the strong 5HT-antagonism compared to Clomipramine. I suppose that's the pharmacological difference which makes Clomipramine superior... ?

Clomipramine exhibits some antagonism of dopamine D1, D2 and D3 receptors... can one expect some clinical & therapeutic benefits from this?

Clomipramine acts as a functional (potent!) inhibitor of acid sphingomyelinase (FIASMA): http://en.wikipedia.org/wiki/FIASMA
Some interesting graphs regarding antidepressant FIASMAs: http://d-nb.info/1011278227/34

Who here has been on Clomipramine and what were your experiences with it?

Most psychiatrists would tell you that the "gold standard" antidepressant is imipramine. The effectiveness of all antidepressants is measured when compared to imipramine. It is the oldest, and it is a very "dirty" drug in the sense that it works via multiple pathways. Extremely strong serotonin reuptake inhibition, very strong norepinephrine reuptake inhibition, D2 receptor agonist, increases the genetic expression of Mu opioid receptors, muscarinic receptor antagonist, which in itself has potent antidepressant effect, etc. The potency and non-selectiveness is what makes it so effective. Imipramine is the drug os last resort when all the SSRIs and SNRIs have been tried and failed.

Although imipramine is far more effective to treat melancholic and anxious depression. For apathetic depression, the gold standard are the MAOIs

Depression --> SSRIs, SNRI

Depression + anhedonia --> MAOIs

Severe depression --> imipramine

They tried to develop drugs for depression with anhedonia besides the MAOIs because of the many drug interactions and side effects of the MAOIs. Examples of this would be the NDRIs, amineptine and nomifensine. But issues of addiction and severe hepatotoxicity limited the effectiveness of these drugs, some cases involving severe liver failure requiring liver transplantation.
 
Most psychiatrists would tell you that the "gold standard" antidepressant is imipramine. The effectiveness of all antidepressants is measured when compared to imipramine. It is the oldest, and it is a very "dirty" drug in the sense that it works via multiple pathways. Extremely strong serotonin reuptake inhibition, very strong norepinephrine reuptake inhibition, D2 receptor agonist, increases the genetic expression of Mu opioid receptors, muscarinic receptor antagonist, which in itself has potent antidepressant effect, etc. The potency and non-selectiveness is what makes it so effective. Imipramine is the drug os last resort when all the SSRIs and SNRIs have been tried and failed.

Although imipramine is far more effective to treat melancholic and anxious depression. For apathetic depression, the gold standard are the MAOIs

Depression --> SSRIs, SNRI

Depression + anhedonia --> MAOIs

Severe depression --> imipramine

They tried to develop drugs for depression with anhedonia besides the MAOIs because of the many drug interactions and side effects of the MAOIs. Examples of this would be the NDRIs, amineptine and nomifensine. But issues of addiction and severe hepatotoxicity limited the effectiveness of these drugs, some cases involving severe liver failure requiring liver transplantation.
Clomipramine is a stronger drug. See binding affinities.


 
These drugs just have broader activity than the newer (more or less) selective serotonin reuptake inhibitors, and for some this is of benefit. I wouldn't exactly tell that gold standard but certainly this thread renewed my interest in those old tricyclics. Once I wanted to get amitriptyline which the doc denied cause of side effects (?) and prescribed me opipramole. The single most useless antidepressant pill ever, it had nothing near any noticeable effect even when I took three or four time the dosage.

DXM when used low-dose might fit in the same dirty SNRI spectrum, and indeed it can be a potent antidepressant. I loved taking 75mg DXM alongside 150mg venlafaxine in my youth... gave me days flooded with some indescribable yet very nice feeling of satisfaction, curiousity, euphoria, energy, ... of being alive, and in the moment.
 
Just thinking now I'd imagine that the drug has so many main mechanisms that the patient respone would be a hard feat to parse out.
 
Clomipramine is a stronger drug. See binding affinities.



Clomipramine is a stronger reuptake inhibitor of serotonin, but that is not the same as saying that it is a better antidepressant than imipramine. The latter has a lot of functions besides inhibiting serotonin and norepinephrine reuptake, like stimulating monoamine receptors and effects on the opioidergic systems.

Also, affinity is not the same as potency. Affinity is just a general indicator of potency, but half inhibitory maximum is a much better indicator of potency. The reason why IC50 is generally not used much is because it requires you to know the experimental conditions, like substrate concentration. So it is difficult to compare drugs using this measure. Affinity is much more universal, which is why it is used. But affinity is a poor measure of potency. For instance cocaine is nothing special when it comes to affinity to the dopamine transporter compared to, say, anfonelic acid. And yet, pretty much everyone who has used both will tell you that cocaine is much more euphoric. That is because cocaine inhibits DAT in the open forward conformation by inhibiting DATs hydrogen bond, which is a particulary effective way of stopping DAT from doing it's job. As another example, moclobemide, the RIMA used to treat depression, has an insignificant affinity for MAO of 200 Um. That is so weak that it is considered insignificant. And yet, moclobemide is effective at inhibiting MAO-A. We know that it is because moclobemide when combined with SSRIs induce severe serotonin syndrome. If it were not effective, then it wouldn't induce ST when combined with therapeutic doses of SSRIs.

There are many, many factors that determine how potent a drug is besides just affinity, such as: resistance to hydrolysis by hydrochloric acid in the stomach, absorption through the G.I tract, degree of first by-pass metabolism in the liver, whether it induces or inhibits liver enzymes and what type, level of protein plasma binding in blood, and binding profile to the receptor or enzyme that it targets. In general, orally active potent drugs tend to be small molecules of a non-polar chemical configuration, with low degree of first by-pass metabolism, relatively low protein plasma binding and low nanomolar affinity for the target. Examples would be tghe SSRI escitalopram and the MAOI, rasagiline. Being lipophilic is also important as most cells have lipid layers, and crossing them is important for a molecule to reach it's target site.
 
Top