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Dr. Bob is Robert Hsiung, MD,
[email protected]Shown: posts 1 to 15 of 15. This is the beginning of the thread.
Posted by J Kelly on May 21, 2016, at 7:59:49
Excuse my ignorance but what is dopamine antagonism? Does this mean dopamine is being released or inhibited?
This came up on another thread, I believe it was said that Zyprexa is a dopamine antagonist and perphenazine isn't. I need dopamine so while I want to reduce or d/c Zyprexa, I'm hesitant to do so if its increasing dopamine.
How does perphenazine compare to Zyprexa in terms of dopamine?
Thanks,
Jade
Ps- My goal here is to lose weight but not at the cost of managing my depression
Posted by linkadge on May 21, 2016, at 15:42:54
In reply to Dopamine antagonism, posted by J Kelly on May 21, 2016, at 7:59:49
Both Zyprexa and perphenazine are dopamine antagonists. But, they are also (to some extent) serotonin antagonists. Some of the clinical effect is due to dopamine antagonism, some is due to serotonin antagonism.
A dopamine (receptor) antagonist, is something that blocks a dopamine receptor. So, while the same amount of dopamine may be released by the brain the dopamine signal is not completed as the post synaptic receptor (which is activated by the dopamine) is blocked.
Its like an antihistamine. The antihistamine blocks the histamine which is released in an allergic reaction. So, while the same amount of histamine is floating around, you don't have the allergic reaction as the histamine receptors which are normally activated by histamine are blocked.
Now, there are different subtypes of dopamine receptors (like d1, d2, d3 etc) which have different functions in different parts of the brain. Different drugs block (or don't block) these different dopamine receptors to varying degrees.
Posted by J Kelly on May 21, 2016, at 17:35:12
In reply to Re: Dopamine antagonism, posted by linkadge on May 21, 2016, at 15:42:54
> Both Zyprexa and perphenazine are dopamine antagonists. But, they are also (to some extent) serotonin antagonists. Some of the clinical effect is due to dopamine antagonism, some is due to serotonin antagonism.
>
> A dopamine (receptor) antagonist, is something that blocks a dopamine receptor. So, while the same amount of dopamine may be released by the brain the dopamine signal is not completed as the post synaptic receptor (which is activated by the dopamine) is blocked.
>
> Its like an antihistamine. The antihistamine blocks the histamine which is released in an allergic reaction. So, while the same amount of histamine is floating around, you don't have the allergic reaction as the histamine receptors which are normally activated by histamine are blocked.
>
> Now, there are different subtypes of dopamine receptors (like d1, d2, d3 etc) which have different functions in different parts of the brain. Different drugs block (or don't block) these different dopamine receptors to varying degrees.
>
>Just so I'm clear, a dopamine antagonist (like Zyprexa) means less dopamine available, correct? Why would anyone want less dopamine?
Thanks, Jade
Posted by Christ_empowered on May 21, 2016, at 21:36:20
In reply to Re: Dopamine antagonism » linkadge, posted by J Kelly on May 21, 2016, at 17:35:12
hi. Here's the story....
The first antipsychotic--trade name: Thorazine--was originally used in pre-operative sedative cocktails. Using Thorazine at low doses meant lower doses of opiates and barbiturates, which meant fewer problems with suppressing breathing and less time recovering from sedation. Now, the patients treated with Thorazine seemed calm and a bit indifferent, but not slowed down...so...
...they used it in asylums. First lower doses, then higher doses, then they did studies using wide ranges of doses. Eventually, Thorazine was approved as the first tranquilizer with the ability to help schizophrenic and manic patients. The effect was initially referred to as a "chemical lobotomy," because when Thorazine worked, it worked like an ideal lobotomy: the patient was calmer, but not over-sedated, and they gradually lost interest in their psychotic processes.
From day 1, it was apparent that Thorazine could induce Parkinson's-type symptoms, so it obviously had an effect on dopamine. Turns out...whether or not Schizophrenia and other psychotic problems are actually *caused* by dopamine dysfunction, blocking D2 receptors will calm people (and animals) down, often without too much sedation. If too much is given, then you start getting twitches and such...
Anyway, since the days of Thorazine and the other phenothiazines (which include perphenazine, btw), researches have looked for drugs that block D2 receptors in treating psychotic states. Because the drugs are basically tranquilizers--give anybody an antipsychotic and they'll calm down--tests in animals look for key effects that indicate dopamine blockade.
As for why you'd want to block off those dopamine receptors...well...a lot of people don't. That's why there are long acting injections of AP/AAP drugs that can be given by court order. The older drugs, in particular, could cause severe depression ("neuroleptic induced dysphoria").The newer drugs, and moderate doses of some older ones, aren't so bad. I take 30mgs/Abilify. That's roughly equal to 400mgs/Thorazine. But if I took 400mgs/Thorazine, I'd probably be twitching and depressed. So, the newer drugs get the job done, but they're more tolerable.
Some people with depression need what a neuroleptic offers--a bit of apathy, distance between themselves and their emotional processes--either alone or in a cocktail. Back in the day, there were combo pills with 1 part amphetamine and 1 part neuroleptic. ThoraDex, StelaDex (stelazine and dexedrine), Eskatrol, etc. Sounds odd today, but these drugs functioned a lot like modern AD, but they worked faster and could be euphoric. One drug combined Stelazine and Parnate in a fixed ration.
So...yeah...neuroleptics/major tranquilizers are odd drugs. Some people need them (I'm raising my hand right now), and even those who don't have bipolar I or schizophrenia can benefit from using them, at least for a while. The modern ones are more tolerable. Higher doses can spell trouble for anybody, but especially people with mood disorders.
Hope this helps!
Posted by J Kelly on May 22, 2016, at 3:51:07
In reply to Re: Dopamine antagonism, posted by Christ_empowered on May 21, 2016, at 21:36:20
Hi CE,
It helped a lot!! Thank you for the detailed post, I understand the subject much better now. Obviously you've done your homework :)
Jade
Posted by Horse on May 23, 2016, at 2:05:59
In reply to Dopamine antagonism, posted by J Kelly on May 21, 2016, at 7:59:49
I think, but I really don't know, so I'm not sure why I'm speaking up, the appeal of Abilify is that it doesn't just inhibit (antagonize?) dopamine. However, it's a real weight gainer.
I've benefited from risperidone at a tiny dose without significant effect on my weight. But generally I don't respond to AAP's. Stimulant add-ons or stimulating ADs are best for me. Wellbutrin. Right now I take nuvigil with brintellix.
Oh, I remember you're on a maoi, so you're options are limited. Maybe low doses? Good luck :)))
Posted by SLS on May 23, 2016, at 9:18:35
In reply to Re: Dopamine antagonism » linkadge, posted by J Kelly on May 21, 2016, at 17:35:12
Hi, Jade.
> Just so I'm clear, a dopamine antagonist (like Zyprexa) means less dopamine available, correct?
A direct antagonist binds to a receptor and blocks it. It is not a reuptake inhibitor. In general, anything that binds to a receptor is called a ligand. Ligands are divided into categories, based upon their action at the receptor. Agonists stimulate, while antagonists and inverse agonists inhibit.
As weird as this sounds, there is actually more dopamine available when using neuroleptic antipsychotics. This occurs because the drug binds to pre-synaptic receptors along with post-synaptic receptors. (Abilify might be an exception). The antagonism of the pre-synaptic receptors convinces the neuron to manufacture and release more dopamine. Although more dopamine is available, the antipsychotic prevents the post-synaptic neuron from "seeing" it because the receptors are blocked by the antagonist.
- Scott
Posted by rjlockhart37 on May 23, 2016, at 22:20:42
In reply to Re: Dopamine antagonism » linkadge, posted by J Kelly on May 21, 2016, at 17:35:12
i've taken zyprexa for years, oringally when i came here in 03 i was looking at stimulants that increase dopamine, but sometimes dopamine can make you irrtible and paranoid, it's the pleasure chemical but yes it has other functions in the brain, motor skills, speech, memory, more awareness about things (too much = paranoia) but zyprexa wipes all paranoia out, but at the same time some dopamine levels are lowered, but i've taken it for year my brain adapted to it, now when i don't take zyprexa i have too much dopamine and irrtiblity.....
Posted by J Kelly on May 24, 2016, at 5:15:22
In reply to Re: Dopamine antagonism » J Kelly, posted by SLS on May 23, 2016, at 9:18:35
> Hi, Jade.
>
> > Just so I'm clear, a dopamine antagonist (like Zyprexa) means less dopamine available, correct?
>
> A direct antagonist binds to a receptor and blocks it. It is not a reuptake inhibitor. In general, anything that binds to a receptor is called a ligand. Ligands are divided into categories, based upon their action at the receptor. Agonists stimulate, while antagonists and inverse agonists inhibit.
>
> As weird as this sounds, there is actually more dopamine available when using neuroleptic antipsychotics. This occurs because the drug binds to pre-synaptic receptors along with post-synaptic receptors. (Abilify might be an exception). The antagonism of the pre-synaptic receptors convinces the neuron to manufacture and release more dopamine. Although more dopamine is available, the antipsychotic prevents the post-synaptic neuron from "seeing" it because the receptors are blocked by the antagonist.
>
>
> - Scott
>Hi,
So is it a wash then? Or does Zyprexa = less available/useable dopamine?
Jade
Posted by J Kelly on May 24, 2016, at 5:18:43
In reply to Re: Dopamine antagonism, posted by rjlockhart37 on May 23, 2016, at 22:20:42
> i've taken zyprexa for years, oringally when i came here in 03 i was looking at stimulants that increase dopamine, but sometimes dopamine can make you irrtible and paranoid, it's the pleasure chemical but yes it has other functions in the brain, motor skills, speech, memory, more awareness about things (too much = paranoia) but zyprexa wipes all paranoia out, but at the same time some dopamine levels are lowered, but i've taken it for year my brain adapted to it, now when i don't take zyprexa i have too much dopamine and irrtiblity.....
>
>Hi rj,
Do you think Zyprexa "wipes out all paranoia" even at low doses, say 2.5mg per day?
Jade
Posted by Christ_empowered on May 24, 2016, at 6:14:16
In reply to Re: Dopamine antagonism, posted by J Kelly on May 24, 2016, at 5:18:43
hey. I looked it up, and 2.5mgs/zyprexa is roughly=100mgs/thorazine. 100mgs/thorazine is a little low for a genuine antipsychotic/anti-manic effect, but well within the range for agitation, anxiety, etc.
Posted by SLS on May 24, 2016, at 7:05:46
In reply to Re: Dopamine antagonism » SLS, posted by J Kelly on May 24, 2016, at 5:15:22
> > Hi, Jade.
> >
> > > Just so I'm clear, a dopamine antagonist (like Zyprexa) means less dopamine available, correct?
> >
> > A direct antagonist binds to a receptor and blocks it. It is not a reuptake inhibitor. In general, anything that binds to a receptor is called a ligand. Ligands are divided into categories, based upon their action at the receptor. Agonists stimulate, while antagonists and inverse agonists inhibit.
> >
> > As weird as this sounds, there is actually more dopamine available when using neuroleptic antipsychotics. This occurs because the drug binds to pre-synaptic receptors along with post-synaptic receptors. (Abilify might be an exception). The antagonism of the pre-synaptic receptors convinces the neuron to manufacture and release more dopamine. Although more dopamine is available, the antipsychotic prevents the post-synaptic neuron from "seeing" it because the receptors are blocked by the antagonist.
> >
> >
> > - Scott
> >
>
> Hi,
>
> So is it a wash then?No. Blocking the postsynaptic receptors prevents any dopamine from stimulating them, depending on the binding affinity (stickiness) of the drug, and its concentration.
> Or does Zyprexa = less available/useable dopamine?
Think of receptors as being polka-dots on the surface of the neuronal membrane. Each can be stimulated by an agonist or inhibited (blocked) by an antagonist. If most of the polka-dots are blocked by the attachment of a sticky antagonist, it doesn't matter how much dopamine is floating around. In a way, the receptors are acting like magnets. Dopamine and drug ligands are also like magnets. The stronger the magnet, the more difficult it is for another magnet to knock it off.
Zyprexa is a molecule that acts as a ligand at dopamine receptors. The strength of the Zyprexa molecule's magnet (binding affinity), and how many molecules are competing for receptor occupancy help determine the dosage necessary for therapeutic effect.
Why most antipsychotics increase the release of dopamine involves the blockade of presynaptic autoreceptors. If you block presynaptic receptors, the presynaptic neuron does not detect intrasynaptic dopamine, and is convinced that it must make and release more. However, it really doesn't matter how much of this released dopamine is available if the the postsynaptic receptors are blocked from binding it.
- Scott
Posted by J Kelly on May 24, 2016, at 17:51:14
In reply to Re: Dopamine antagonism, posted by Christ_empowered on May 24, 2016, at 6:14:16
> hey. I looked it up, and 2.5mgs/zyprexa is roughly=100mgs/thorazine. 100mgs/thorazine is a little low for a genuine antipsychotic/anti-manic effect, but well within the range for agitation, anxiety, etc.
>
>I'm gonna take 5-10mg Zyprexa then. I'm trying to avoid psychosis while on Nardil.
Thanks,
Jade
Posted by Christ_empowered on May 24, 2016, at 18:35:38
In reply to Re: Dopamine antagonism » Christ_empowered, posted by J Kelly on May 24, 2016, at 17:51:14
looked it up again to be sure. its actually 2mgs haldol=100mgs thorazine=5mgs zyprexa.
I think for mania and such 200mgs/Thorazine was fairly standard, with other stuff on board. 300-600 was common for anti-psychotic effects.
Posted by J Kelly on May 24, 2016, at 21:56:44
In reply to Re: Dopamine antagonism » J Kelly, posted by SLS on May 24, 2016, at 7:05:46
> > > Hi, Jade.
> > >
> > > > Just so I'm clear, a dopamine antagonist (like Zyprexa) means less dopamine available, correct?
> > >
> > > A direct antagonist binds to a receptor and blocks it. It is not a reuptake inhibitor. In general, anything that binds to a receptor is called a ligand. Ligands are divided into categories, based upon their action at the receptor. Agonists stimulate, while antagonists and inverse agonists inhibit.
> > >
> > > As weird as this sounds, there is actually more dopamine available when using neuroleptic antipsychotics. This occurs because the drug binds to pre-synaptic receptors along with post-synaptic receptors. (Abilify might be an exception). The antagonism of the pre-synaptic receptors convinces the neuron to manufacture and release more dopamine. Although more dopamine is available, the antipsychotic prevents the post-synaptic neuron from "seeing" it because the receptors are blocked by the antagonist.
> > >
> > >
> > > - Scott
> > >
> >
> > Hi,
> >
> > So is it a wash then?
>
> No. Blocking the postsynaptic receptors prevents any dopamine from stimulating them, depending on the binding affinity (stickiness) of the drug, and its concentration.
>
> > Or does Zyprexa = less available/useable dopamine?
>
> Think of receptors as being polka-dots on the surface of the neuronal membrane. Each can be stimulated by an agonist or inhibited (blocked) by an antagonist. If most of the polka-dots are blocked by the attachment of a sticky antagonist, it doesn't matter how much dopamine is floating around. In a way, the receptors are acting like magnets. Dopamine and drug ligands are also like magnets. The stronger the magnet, the more difficult it is for another magnet to knock it off.
>
> Zyprexa is a molecule that acts as a ligand at dopamine receptors. The strength of the Zyprexa molecule's magnet (binding affinity), and how many molecules are competing for receptor occupancy help determine the dosage necessary for therapeutic effect.
>
> Why most antipsychotics increase the release of dopamine involves the blockade of presynaptic autoreceptors. If you block presynaptic receptors, the presynaptic neuron does not detect intrasynaptic dopamine, and is convinced that it must make and release more. However, it really doesn't matter how much of this released dopamine is available if the the postsynaptic receptors are blocked from binding it.
>
>
> - ScottThank you for explaining :)
Jade
This is the end of the thread.
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Dr. Bob is Robert Hsiung, MD,
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