interesting conversation I had with a pharmacist

[milkman]

I spoke to a pharmacist who ive known for years and he said the OLDER antipsychotics are actually MORE effective for the voices, paranoia etc. mainly for the positive symptoms of schizophrenia BUT he said the reason why they are not used much now days is coz of the side effects mainly EPS and TD. He also said some of the new ones such as seroquel and abilify are pretty weak. appparently the dopamine blockade is STRONGER with the old ones while the new ones have been watered down so they dont cause as much EPS and TD as with the older ones. is this true? what do you guys think? are the older ones actually more stronger at treating the voices, paranoia etc.? plz express ur opinions!

[Laume]

My dad was a pharmacist (well a Bipolar-Schizoaffective disorder one) and when he went downhill, his pdoc put him on risperidone against his will (he had blinded himslef my then so was pretty unable to help himself).

He told me that the side-effects of the newer APs were just as bad as the older APs but the difference was a lot of stigma attached to the old school ones and the drug companies wanting to make more $$$ off patented stuff (this was about 10 years ago).

He developed very bad TD on a relatively low dose of risperidone (4-5 mg) and was then switched to an old school one (name escapes me right now) where he did better on when he was med compliant.

Everyone has their own opinion on this stuff

[MarkP]

Yeah, basically, that's the truth. The new ones are significantly weaker, and they tend to cause diabetes, weight gain, etc. haloperidol is still the 'gold standard' for treatment of schizophrenia.

4-5mg risperidone is not a low dose by any means. That's actually at the higher end of the overall dosing range.

[Aurochs]

The prevailing theory is that atypical antipsychotics show fewer EPS because they antagonize serotonin receptors - whether this directly contributes to fewer EPS or indirectly by exerting antipsychotic effects (and allowing a lower D₂ affinity for similar therapeutic effect) isn't certain. Nor is there agreement that 5-HT_2A antagonism has anything at all to do with anything.

And if atypicals are less effective than typicals, their lower D₂ affinty is not the (sole) reason. The undisputed king of antipsychotic effectiveness is clozapine, an atypical with a low D₂ affinity. Olanzapine seems to be on par with most typicals for effectiveness, despite its considerably lower D₂ affinity. And risperidone has similar D₂ affinity to typical antipsychotics.

Pharmacists are not trained to prescribe - they are trained to dispense, which is a completely different ball game. While a bad pdoc may not know how effective a given medication might be, a pharmacist would be worse because that's not part of his job. Also, I wouldn't trust the medical advice of anyone who would willingly sell me Head-On.

[SashaSue]

From what I've seen, actual clinical studies addressing this issue have been pretty inconclusive.

[tryp]

According to my pharmacology prof, the reason the AAPs are an improvement over the APs is their capacity to also treat the negative symptoms of schizophrenia.

One argument that I've heard about the APs v. AAPs in terms of side effects is that the reason the APs are seen to have more side effects is that when they were being used widely (before AAPs), docs were not as careful about dosage and indications - they just hit everyone in the institution with a huge dose of haldol or thorazine or whatever. So it's no wonder the side effects were terrible. The dosages were just too high.

[etkearne]

After reading numerous articles on the subject, other than Seroquel and Clozapine, which affect D2 differently, a drug must occupy at least 60% of the D2 receptor sites for effectiveness. All antipsychotics can do this. It is just a matter of dose (like poster above said- they used like 25mg of Haldol on people which is insane) and the combination of other receptor blockade to mask the EPS. Take olanzapine. By D2 comparison, it stands its ground with typicals and with Risperidone. My chart says that 10mg Zyprexa (70% D2 blockade)= 3mg Risperidone = 2 mg Haldol. But, the point is that Zyprexa also antagonizes M1 and H1, which tend to counteract the EPS, especially the akathisia. Risperidone offers some alpha-adrenaline blocking, and so does Haldol (to a lesser extent), but they will yield EPS at lower doses than Zyprexa.

Personally, I have taken 20, 30 mg of Zyprexa without any EPS. At 40, however, I experienced full-blown EPS and stereotyped 1970s mental hospital behavior. According to my chart, that is equivalent to 7mg of Haldol and around 12-14mg of Risperidone. Pretty heavy doses. But, I have read of people getting 100mg of Haldol in hospitals. That would be pure torture, based on how I felt on the equivalent of 7mg of Haldol.

[Aurochs]

Yes, antipsychotic effects seem to correlate with a certain level of striatal D₂ occupancy. However, I am not aware of any correlation between M₁/H₁ occupancy and EPS. Haloperidol is a strong M₁ antagonist, and chlorpromazine is a very strong antihistamine (most antipsychotics are - they were developed from antihistamine sedatives, after all). Both drugs are notorious for causing EPS.

If H₁ antagonism prevented akathesia, we would expect Abilify to be much less liable to cause it than it actually is, especially when compared to haloperidol (Abilify has nanomolar affinity at the H₁ receptor, versus Haldol's micromolar affinity), but the two are roughly on par in terms of akathesia rates. M₁ affinity can't be called in either, because Haldol loves that receptor but Abilify doesn't.

[etkearne]

Yes, antipsychotic effects seem to correlate with a certain level of striatal D₂ occupancy. However, I am not aware of any correlation between M₁/H₁ occupancy and EPS. Haloperidol is a strong M₁ antagonist, and chlorpromazine is a very strong antihistamine (most antipsychotics are - they were developed from antihistamine sedatives, after all). Both drugs are notorious for causing EPS.

If H₁ antagonism prevented akathesia, we would expect Abilify to be much less liable to cause it than it actually is, especially when compared to haloperidol (Abilify has nanomolar affinity at the H₁ receptor, versus Haldol's micromolar affinity), but the two are roughly on par in terms of akathesia rates. M₁ affinity can't be called in either, because Haldol loves that receptor but Abilify doesn't.

antipsychotics.bmpslide21BMP.bmp

Haldol barely antagonizes M1 (see Table and Chart). Also note, numerically, how weakly Abilify binds to H1 and M1 compared to the other Atypicals.

I think for in the case of Thorazine, it is just the fact that 1) It does strongly antagonize D2 (I don't have the numbers) and 2) It was given at enormous dosages to inpatients for years. Like the story I told, even an antipsychotic that seems EPS free at low doses (even Zyprexa) can turn into an EPS nightmare past a certain point.

From everything I have read, M1 especially is key in masking EPS. In fact, they often deliver Haldol with an antihistamine, since some antihistamines, like Diphenhydramine HCl are H1 and M1 antagonists.

Funny note: For PRN antipsychotic use, I prefer threshold (meaning 60% D2 site occupation) doses of typicals to atypicals. I am able to function normally without all of the sedation and slurring of the atypicals. I save some Prochlorperazine in my "Take to work/school" medicine bottle for emergencies. I also put Abilify in there, even though I have never had relief of psychotic symptoms from that stuff, even at akathisia related dosages. Anyone have any ideas on that??

ALSO! Check out this awesome article that debates what constitutes atypicality.

http://consortiumcon...eptors_2003.pdf

EDIT: I found it- Thorazine has binding affinity pK value of 25 for D2, 130 for M1, 28 for H1. So, at doses of 100mg and such, which people receive regularly, that is quite a lot of dopamine blockade. Thorazine is around half the potency of Zyprexa for D2. So 100mg of Thorazine would be like taking 50mg of Zyprexa (in terms of D2 effects- EPS, prolactin, etc.) That is pretty crazy.

[Aurochs]

I apologize for the mixup re: haloperidol's M₁ affinity, which was me somehow screwing up the data I pulled from PDSP. I used to know this shit, damnit.

Antihistamines and antimuscarinics are used in the treatment of EPS, as you correctly point out. I haven't noticed any correlation between antihistamine effect and lowered risk of EPS - notably, chlorpromazine has similar affinity for both H₁ and D₂ receptors, but much lower affinity for M₁. Some research has been conducted around drugs that target only the M₁ receptor, as blocking it seems to have antipsychotic effects on its own, but it's hard to be selective for M₁ over the other muscarinic receptors. Xanomeline was rejected for clinical trials after the first patients reported unacceptable antimuscarinic side effects.

[etkearne]

I apologize for the mixup re: haloperidol's M₁ affinity, which was me somehow screwing up the data I pulled from PDSP. I used to know this shit, damnit.

Antihistamines and antimuscarinics are used in the treatment of EPS, as you correctly point out. I haven't noticed any correlation between antihistamine effect and lowered risk of EPS - notably, chlorpromazine has similar affinity for both H₁ and D₂ receptors, but much lower affinity for M₁. Some research has been conducted around drugs that target only the M₁ receptor, as blocking it seems to have antipsychotic effects on its own, but it's hard to be selective for M₁ over the other muscarinic receptors. Xanomeline was rejected for clinical trials after the first patients reported unacceptable antimuscarinic side effects.

No need to apologize! I just like to show off those charts I found haha. We're all trying to learn here. Side note- I do hope to work as an math analyst in pharmacology some day not too long from now.

Seriously, though, alot of the reading I have done has also, in addition to what you just said, and to what I said before, indicated two other things that lower EPS:

1. 5-HT2A is possibly responsible for the reduction of EPS as described in the article I posted, since it allows normal dopamine functioning in the "problem" areas that deal with prolactin and motor skills, while leaving the other areas (I forget the term - something cortex) fully antagonized.

2. Some atypicals like Seroquel and Clozapine can do their antagonizing quickly and efficiently, binding tightly but shortly to the D2 receptor, only ever occupying around 30%, as opposed to the 60-80% for other drugs. These two drugs are virtually free of EPS and prolactin problems. Virtually, not 100%.

I might do my master's thesis on antipsychotic binding affinity. I would take in a set of variables for a patient and use mathematical modeling to output the antipsychotic (be it atypical or typical) that would best fit the need of the patient, eliminating some trial and error. It would be useful for GP's who don't have experience in psychiatry and could possibly make a harmful error.

[Aurochs]

Where did those screenshots come from? It looked like some review, but I'm not sure where their information came from or what their conclusions are.

I already noted the 5-HT_2A theory in post #4. It's been widely cited for years, but lately people have started to question it more. My understanding is that there's not a lot of certainty about how important this receptor actually is anymore. I can't recall the results of any studies on selective 5-HT_2A antagonism, though I know they exist - I should probably go looking for them again.

My understanding of your second point is that those two drugs are easily displaced by the radioligands used to measure their occupancy, skewing the measurements and making it appear that they occupy fewer receptors than they actually do. They're also easily displaced by dopamine, which would explain their lower rates of EPS. But if dopamine can push them off so easily, I'm not sure how they actually work - possibly inverse agonism while they ARE bound to the receptor is enough?

I'm nowhere near the level of academic accomplishment that you're at (everything I've learned has been my own curiosity and publicly-available articles, and I've only recently gone back to college), but my ultimate goal is to do research in cell signaling on the molecular level - how the activation or inhibition of a receptor affects the cell itself, and why modifying one receptor system has effects on other systems, is a really interesting field.

Mathematical modeling of drug response sounds like a tall order, and I can't begin to think of how you might go about it. But it sounds like it'd be a lot of fun to work on. =)