Acadia Gives Up On ADP-104-- Maybe It Shouldn't Have
The headline says almost everything: Acadia shares plunge more than 50% on study data for schizophrenia drug. Turns out the drug didn't work at either of the two doses tested.
They should have called me first: their study was flawed.
High plasma levels of NDMC (ranging from 1200-4230 ng/ml), approaching those of clozapine itself, have been observed in humans given clozapine. Moreover, several investigators have shown that the degree to which clozapine is converted to NDMC predicts clinical outcome on multiple measures of cognition, negative and positive symptoms, as well as quality of life. It is noteworthy that the ratio of NDMC to clozapine, rather than absolute levels of either clozapine or NDMC, was found to be the best predictor of a positive clinical outcome. This observation suggests that certain pharmacological properties of clozapine may actually counteract beneficial pharmacology of NDMC.That's the premise. But the premise is wrong, the blood levels and the ratio of NDMC to clozapine are coincidences, they have nothing whatsoever to do with clinical outcome.
The authors try also to make a case that D4 blockade may be involved, or at least cause an "atypical" profile (e.g. low EPs, etc), but Thorazine and Haldol are potent D4 blockers, so there.
I am also aware of the considerable ink and paper spent describing the contributions of serotonergic pathways, but it is categorically true that there does not exist a drug that is a pure 5HT antagonist-- take your pick of subtype-- that works as an antipsychotic.
It is so far without exception that every efficacious antipsychotic has power of significant D2 blockade. Or, said another way, there does not exist any antipsychotic that lacks significant power for D2 blockade. Whatever the contribution of other receptors, it is overwhelmed by the presence, or absence of D2 blockade.
Going from there, the single most important question that can be asked of any antipsychotic is: at what dose does this drug cause significant D2 blockade? Whatever the answer is, it is again certain that at a dose less than that, it will fail to provide any efficacy.
The article shows nearly equal D2 antagonist activity for clozapine and for NDMC, and one can conclude dosing will be similar, e.g. 300-500mg/d.
Unfortuantely, NDMC is also a partial agonist at low doses; so the dose needed for D2 blockade will be higher.
Acadia, the drug company, tested NDMC at 100mg/d and 200mg/d. It failed. This is a lot like saying one tested clozapine at 100mg, found significant side effects but no reliable efficacy, and canned it.
Acadia should try again. I am sure they worry that the side effects will get worse, but they won't.
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June 27, 2008 12:48 PM | Posted by : | Reply
If it's just D2 blockade, then why does clozapine have such a different clinical picture (e.g., works when all other meds fail)?
June 27, 2008 3:58 PM | Posted by : | Reply
Its side effect profile is so terrible, that it necessarily is the last option, right? Any drug that is always the last option will appear to be the one that "works when all other meds fail."
Assuming there is one "right" med for every person, each subsequent trial has a greater chance of success. With five atypicals, there is a 20 percent chance that you'll guess right. With each trial, the odds improve, until, finally, there is Clozaril--The one that works when others have failed. Notice that the reason this is not said about Seroqeul is because Seroquel is never the last one tried.
Guessing E every time after A, B, C, and D have failed says nothing about E other than the fact that it was chosen last.
June 28, 2008 12:33 PM | Posted by : | Reply
Considering I have a family member who started at 300mg of Clozaril one year, went off of it, crashed into massive psychosis, and when it was reinstated at 500mg. the psychosis lifted that had disabled the person for 5 months. Another increase recently to 550mg. life has become better, not perfect. Do you still believe the glutamate drug might end up being the one that is most efficacious if it ever enters the market? Thanks for this article.
July 2, 2008 1:11 AM | Posted by : | Reply
You say the side effects won't get worse at a higher dose, but you are forgetting that D2 blockade itself causes EPS and prolactin elevation. It even looks like the antihistaminic and anticholinergic side effects serve to counteract the side effects caused by D2 blockade. If I'm not mistaken, the drugs that cause relatively less D2 blockade and more H1/M1 blockade are the ones that cause the least EPS. Risperdal is the worst of the atypicals when it comes to EPS and is more likely than not only the other atypicals, but also the older drugs to cause prolactin elevation, and it has virtually no affinity for cholinergic receptors.
Is it actually known why clozapine is very unlikely to cause EPS?
July 3, 2008 7:09 AM | Posted by : | Reply
A person I know well recommends psychotherapy which then rules out
the level of sedation of memory these drugs imply..........
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