BobA

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I remember at attending saying to me once that unless someone has been on antipsychotics chronically, "there's no point in using more than Xmg of Haldol because the dopamine receptors get saturated."

However, I can't remember what dose "X" is. I've done a few google scholar searches without much luck.

Does anyone know anything about this?

Thanks!
 

whopper

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I do know in Kaplan and Sadock it's mentioned in extensive detail. Aw nuts, where the heck was it in that book. I didn't bother to buy the newer edition finding it not worth it.

I did happen upon this article.

http://www.springerlink.com/content/t3rhab14hfcy67ht/
 
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BobA

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Whopper was right:
From Kaplan and Saddocks

Table 31.17-3

At about 6mg/day 85-89% of D2 receptors are saturated .

similar to that study you posted.

Interesting that we frequently use such higher doses in clinical practice.
 

strangeglove

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Perhaps higher doses are required in chronic use because of upregulation of D2 receptors secondary to long-term blockade.
 

nitemagi

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I'm going to re-emphasize the oft-neglected concept of the inverted u-curve in oversaturating dopamine, which likely has implications for cognition and positive psychotic sx's as well.

Here's a few papers on it.

http://www.ncbi.nlm.nih.gov/pubmed/3955111
http://www.ncbi.nlm.nih.gov/pubmed/2813809
http://www.ncbi.nlm.nih.gov/pubmed/21531388

The implication? Don't get lost in the illusion that more is always better, and that you need to "annihilate" their hallucinations to reach the sweet spot of optimal function.
 

whopper

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A weird thing. Working in a state psychiatric hospital with forensic (more violent psychotic patients) and long-term facilities (more treatment-resistant cases), there are a few patients who did get better on ultra-high levels of Haldol that did not improve on lower dosages.

Now WTF this was going on despite the above data, I do not know. I do know, however, that if I've tried a bunch of other things, and the patient is lifting up a chair over his head at over 100 lbs (weighted to prevent people from being able to lift it) and the guy is still able to do it and toss it at staff members, and Haldol at 25 mg a day is actually stabilizing him and I tried 6 other antipsychotics, along with lithium and Depakote, I'm going to give the Haldol.

The only theories I got is perhaps the guy was just given typicals for too long and it caused receptor changes, or the person is a hyper-metabolizer of Haldol. There are gene studies that could be done to see if the person is a hyper-metabolizer, but given that it's not reimbursed, I don't see too many doctors ordering it.
 

MedSchoolFool

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Wouldn't ordering a Haldol level be able to indicate if the person is a rapid metabolizer or not?

I have also wondered why we use such large doses of Haldol since at ~2mg you've reached the magic 80% occupancy at D2 receptors. Any more than 80% is theoretically not helping anything.
 

whopper

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Wouldn't ordering a Haldol level be able to indicate if the person is a rapid metabolizer or not?
It could.
 

nitemagi

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Wouldn't ordering a Haldol level be able to indicate if the person is a rapid metabolizer or not?
We'd need good data on therapeutic levels and outcome, which I think does actually exist.
 

Fastball32

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I know everyone here knows that Psychosis is more than just D2 receptors.

Actually, Aripiprazole has the highest D2 affinity, even more so than Haloperidol.

If risk of Tardive Dyskinesia is dose and time dependent, clinically it'd be rare to go above 30mg daily.

That said, I agree with Whopper that we would see more people get better if we push doses above FDA max.
 

OH SYNAPSE

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Doc Samson likely hasn't seen this thread yet, otherwise he would probably have chimed in to remind us about the story of Haldol and sigma receptors. Not sure if the OP was asking about dosing in the context of psychosis vs delirium, but the sigma receptor side of haldol is interesting regardless.

To quote him from the past:

I'm talking specifically about delirium here - I'd switch to something else too if I were treating acute mania or psychosis. For years the haldol naysayers have been saying that >90% of D2 receptors are blocked after 10 mg of Haldol, so why use more doses. Research in the past couple of years has found that they butyrophenones (haldol and droperidol) have an idiosyncratic dose responsive action at the sigma receptors that is neuroprotective in conditions of oxidative stress. In other words, in delirium haldol may actually save neurons.
And:
Refs for the sigma receptor stuff:

Schetz JA, Perez E, Liu R, et al: A prototypical Sigma-1 receptor antagonist protects against brain ischemia. Brain Res 2007; 1181:1–9

Lee IT, Chen S, Schetz JA: An unambiguous assay for the cloned human sigma-1 receptor reveals high affinity interactions with dopamine D4 receptor selective compounds and a distinct structure-affinity relationship for butyrophenones. Eur J Pharmacol 2008; 578:123–136
 

splik

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Actually, Aripiprazole has the highest D2 affinity, even more so than Haloperidol.
Abilify does have a high affinity for D2DR but it is not an antagonist but a partial agonist, thus the effect of its occupancy of D2DR is much less than for haldol.
 

splik

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I believe Paul Janssen who invented haloperidol and got rich off it, never intended it to be used at doses greater than 5mg. if you read the very early literature very low doses were used. This of course was in antipsychotic naive individuals. When he visited one country I cant remember somewhere in the middle east he was shocked to find 120mg of haloperidol routinely being used! Although some people complain about high doses today (and have heard some horror stories), often doses in 1960s and 70s were much higher.
 

Fastball32

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Abilify does have a high affinity for D2DR but it is not an antagonist but a partial agonist, thus the effect of its occupancy of D2DR is much less than for haldol.
Yes, didn't want to state the obvious ;)

The point is that although D2 gets all the glory for being the main antipsychotic receptor, when things get complicated, there's more to alleviating psychosis than D2.
If you look at Clozapine's D2 affinity, it is one of the worst, only better than Quetiapine. Even Ziprasidone has a higher affinity than Olanzapine (just behind Risperidone), and most would agree that Clozapine and Olanzapine are excellent for psychosis.

Also keeping in mind that the newer antipsychotics (Ziprasidone and Aripiprazole) probably have a lower FDA max because when they were released in the early 2000's, the FDA was much more stringent with max dosing. (i.e. Risperidone's FDA max is an incredible 16mg/day, eventhough >6mg/day are usually not more beneficial)
 

splik

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It was very popular to look at other mechanisms of action of antipsychotics (e.g. D4, 5HT2) some years ago but in the past 5 years there seems to have been a swingback to looking at antipsychotic action in terms of D2 blockade.

This paper in particular was responsible as it suggested that atypical antipsychotic action could be explained in terms of fast-dissociation of D2 receptor blockade, including clozapine.
 

Fastball32

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It was very popular to look at other mechanisms of action of antipsychotics (e.g. D4, 5HT2) some years ago but in the past 5 years there seems to have been a swingback to looking at antipsychotic action in terms of D2 blockade.

This paper in particular was responsible as it suggested that atypical antipsychotic action could be explained in terms of fast-dissociation of D2 receptor blockade, including clozapine.

I definitely would not disagree that D2 is the leading receptor theory for antipsychotics and blocking it should help most individuals...we agree that the commonality between all "antipsychotics" are that they block D2.
The Fast Dissociation theory does give a possible explanation for the lack of correlation between D2 affinity with antipsychotic effects in atypicals, but believing that D2 blockade alone would fix psychosis would almost imply that raising antipsychotics should treat all individuals. Newer atypicals such as Asenapine are marketing it's high affinity with multiple receptors.
One of the reasons why I like Psychiatry is that it is the last frontier of Medicine.
Love the great discussion!
 
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The Dopamine Hypothesis of Schizophrenia: An historical and philosophical analysis
The dopamine (DA) hypothesis of schizophrenia (DHS) has, since its inception over 30 years ago, been among the most prominent etiologic theories in psychiatry. This essay begins by summarizing the history of its emergence and efforts to empirically test it through the examination of (i) cerebrospinal fluid DA metabolites, (ii) neuroendocrine measures, (iii) clinical response to psychostimulants, (iv) brain levels of DA and its metabolites, (v) brain studies of DA receptors, and (vi) genetic association studies. We then examine how successful the DHS has been and by what criteria its performance should be evaluated. In this process, it is critical to distinguish the etiological DHS from the pharmacological DA hypothesis of neuroleptic action. Although the DHS stimulated much science, most efforts to empirically validate it have failed, in contrast with the well-supported pharmacological DA hypothesis of neuroleptic action. Nonetheless, the DHS has held the status of a scientific paradigm defended by some with great avidity. Like other temporally extended theories, the DHS in its most general form is relatively nonspecific and protean in nature. In its evolution through successive more specific forms, often embodying ad hoc modifications of subsidiary hypotheses, it became very difficult to falsify. Although stimulating much research, it has not produced a progressive research program generating various novel and confirmed predictions about schizophrenia. For most of its history, the DHS has lacked a viable competing alternative theory against which it could be incisively compared. Sociological factors, especially the rise to prominence of the biological psychiatry movement, and the conflation of the DHS and the DA theory of antipsychotic drug action have probably played an important role in its persistence. Psychiatry needs theories with higher levels of specificity and falsifiability. As the science of psychiatry matures, the field needs to become more self-critical about the validity of its theories.
http://muse.jhu.edu/journals/philosophy_psychiatry_and_psychology/v018/18.1.kendler.html#back

By Ken Kendler, who I saw speak recently, which was pretty great. Anyways, I think this is a nice read, too.
 

whopper

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If you look at Clozapine's D2 affinity, it is one of the worst, only better than Quetiapine.
Very true. D2 blockage is only part of the story. The problem is we don't know what much of the rest of the story is to the degree where we can exploit it into a practical tool for treatment other than serotonin's involvement in psychosis.