June 25, 2008

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.

ADP-104 is an active metabolite of clozapine: N-desmethylclozapine.  The authors of a review write

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.


If it's just D2 blockade, t... (Below threshold)

June 27, 2008 12:48 PM | Posted by Steve: | 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)?

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Its side effect profile is ... (Below threshold)

June 27, 2008 3:58 PM | Posted by Anonymous: | 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.

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Considering I have a family... (Below threshold)

June 28, 2008 12:33 PM | Posted by Stephany: | 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.

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You say the side effects wo... (Below threshold)

July 2, 2008 1:11 AM | Posted by acute_mania: | 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?

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A person I know well recomm... (Below threshold)

July 3, 2008 7:09 AM | Posted by Diane Abus: | 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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The atypical's proclivity... (Below threshold)

June 25, 2010 4:24 PM | Posted by Harry Horton: | Reply

The atypical's proclivity to cause hyperglycemia and diabetes along with other metabolic syndrome conditions, with this subject in regards the following article from American Journal of Psychiatry February 2004 has some interesting information that could be further expounded upon and explored with followup larger studies. The research study: "A Prospecive Study of Impairment of Glucose Control caused by clozapine without changes in insulin resistance" Oliver D. Howes.
An excerpt from the article: "The baseline insulin resistance level was within the upper quintile of the range of insulin resistance levels seen in healthy control subjects, indicating a greater risk of developing diabetes. THe similarity of insulin resistance levels to those found in previous reports (3) suggests the patients show a pre existing insulin insensitivity that may be related to previous treatment, schizophrenia, or raised body mass index." End quote. Later Howes stated in the study: "An alternative mechanism would be a direct drug effect on glucose regulation. Clozapine reduces glucose uptake in neuronal cells (7). THis would reset the plasma glucose levels that glucose sensing neurons accept as normal, meaning the glucose levels is perceived as lower than it is, and resulting in compensatory increases in glucose levels. THis mechanism would explain the rapid increase in plasma glucose levels independent of changes in insulin resistance." End quote.
An additional article that has relevance to this latter Howes alternative ponderance: "Role for GLucose sensing neurons in Type II Diabetes Identified" Science Daily (August 30, 2007). Quote from the article:"What is apparently happening" says Parton, "is that an increase of the activity of mitochondrial uncoupling protein 2 (UCP2) is behind the loss of glucose sensing ability in the POMC neurons. Increased activity of UCP2 is known to cause a loss of glucose sensing ability in POMC neurons." end quote. THis second article seems to give an interesting answer to Howes' alternative mechanism processes. 70% of patients that take some of the atypicals have no effect on glucose levels, at least in the first six months while 30% get some sort of hyperglycemic states. 1-5% actually have wildly out of ocntrol glucose dysregulation with a segement of that group not being able to retain glucose control. Insulin resistance levels that are high though still normal seem to point at energy homeostasis problems existing previous to taking the drugs as a basic factor for developing hyperglycemia and diabetes in some cases. With the Howes study's facts in consideration. In any case, it seems prudent that his results from this study could be further expanded in larger studies in order to better categorize the prevalence of his findings.

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Good article and I like thi... (Below threshold)

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