Hipster "Teh" Hits a Staid Pharma-Journal

The Teh finally hit the conservative pages of Scrip World Pharmaceutical News.

Wyeth's new antipsychotic receives FDA non-approvable letter after fatality

August 13, 2007
Scrip

The US FDA has issued a non-approvable letter for Wyeth/Solvay's new-generation atypical antipsychotic bifeprunox, which was under review for the acute treatment of schizophrenia and the maintenance of stable adult patients.

Wyeth's share price on teh New York Stock Exchange closed at $46.59, down by 6% on August 10th. (emphasis mine)

OK, it may just be a typo, but I'd like to think it's an oh-so-hip ironic reference to Teh NYSE.

I will inflict you with a little sidebar on the drug...just because I can:

The majority of atypical antipsychotics on the market are dopamine receptor antagonists. Bifeprunox is a partial agonist of the D2 dopamine receptor, a G-protein coupled receptor (GPCR). Like aripiprazole (Abilify), another D2 partial agonist, bifeprunox is believed to act as a dopamine stabilizer, that is, decreasing overactive dopaminergic response in some areas of the brain and increasing it in others.

The FDA issued the non-approval letter because of a patient's death (multi-organ failure) in an acute (six-week) trial. It was noted that the case was complex and that it is not known if the patient's death was related to the drug.

Yeah, so that explanation of D2 partial agonists was teh lame. You know what I have to say to that?

Meh.

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"...bifeprunox is believed to act as a dopamine stabilizer, that is, DESCREASING overactive dopaminergic response in some areas of the brain and increasing it in others."

Are you creasing the DES, or dessing the crease?

Is there a marked difference in affinity or activity between those 2 drugs? Is the subtype specificity of the drug, along with the distribution of dopamine receptor subtypes in different areas of the brain what's responsible for the stabilizing effects in patients? Why target the D2 subtype specifically instead of other subtypes?
I know that's too many questions but you just gave tidbits about one of my passions, please tell more!

Are you creasing the DES or...

Oooooh, brilliant catch! I stand typographically corrected.

Oh, and I know you are, but what am I? :^p

Is there a marked difference in affinity or activity between those 2 drugs?

Excellent questions, Brigit!

Based on what I can quickly glean from the literature, and not take too much time from my day job,* the affinities of bifeprunox and aripiprazole for the D2 receptor are about the same, ~0.3 nM for in vitro systems FWTIW. Their affinities for for the 5-HT1A receptor are fairly similar,too, if I recall correctly. However, they appear to have different affinities to the D3 receptor which may in turn translate to different effects on downstream activation of phosphorylation through the MAP kinase pathway. Those differences in signaling could very well account for differences in efficacy, etc. And that's not to mention distribution of the receptors and their sub-types throughout the brain. In other words, it's pretty complex, and I fear I am not the one to write a review article in a comment. :^) I hope you'll forgive me if I cop out and recommend a Medline search on the topic.

*I can justify the time a bit since we work on GPCRs in my group, and and we support projects in neuroscience.

And to highlight the complexity of the partial agonist aripiprazole, check out the following abstract from Urban et al. (2007) Neuropsychopharmacology 32, 67-77:

Aripiprazole is a unique atypical antipsychotic drug with an excellent side-effect profile presumed, in part, to be due to lack of typical D2 dopamine receptor antagonist properties. Whether aripiprazole is a typical D2 partial agonist, or a functionally selective D2 ligand, remains controversial (eg D2-mediated inhibition of adenylate cyclase is system dependent; aripiprazole antagonizes D2 receptor-mediated G-protein-coupled inwardly rectifying potassium channels and guanosine triphosphate nucleotide (GTP)S coupling). The current study examined the D2L receptor binding properties of aripiprazole, as well as the effects of the drug on three downstream D2 receptor-mediated functional effectors: mitogen-activated protein kinase (MAPK) phosphorylation, potentiation of arachidonic acid (AA) release, and D2 receptor internalization. Unlike quinpirole (a full D2 agonist) or (-)3PPP (S(-)-3-(3-hydroxyphenyl)-N-propylpiperidine hydrochloride, a D2 partial agonist), the apparent D2 affinity of aripiprazole was not decreased significantly by GTP. Moreover, full or partial agonists are expected to have Hill slopes <1.0, yet that of aripiprazole was significantly >1.0. Whereas aripiprazole partially activated both the MAPK and AA pathways, its potency vs MAPK phosphorylation was much lower relative to potencies in assays either of AA release or inhibition of cyclic adenosine 3',5'-cyclic monophosphate accumulation. In addition, unlike typical agonists, neither aripiprazole nor (-)3PPP produced significant internalization of the D2L receptor. These data are clear evidence that aripiprazole affects D2L-mediated signaling pathways in a differential manner. The results are consistent with the hypothesis that aripiprazole is a functionally selective D2 ligand rather than a simple partial agonist. Such data may be useful in understanding the novel clinical actions of this drug.

Doc! It's great to see you post even if I have absolutely no clue what you are talking about. Incidentally, I have been reading the Oppenheimer biography...good lord, why didn't you TELL me it contained his "erotic poetry"?! I nearly flung the book across the room!

good lord, why didn't you TELL me it contained his "erotic poetry"?! I nearly flung the book across the room!

What? The "sacred sphincter of their erudition" doesn't do it for you?

"Doc! It's great to see you post even if I have absolutely no clue what you are talking about..."

Why do you hate my writing so much?

Kevin, I enjoy your sacred, erudite sphincter as much as the next girl, but I have been missing Madame Blowfish's shitwitticisms.

Also, this is a funny headline:

Wyeth's new antipsychotic receives FDA non-approvable letter after fatality

To me, this makes it appear as if someone recently hired by Wyeth, Inc. and absolutely free of delusions has received a letter that the U.S. Food and Drug Administration would not approve of.

Sounds like this drug and those like at are the schizophrenia-oriented brothers and sisters of Ritalin -- they stimulate, but only in those not already overstimulated. This explains why so many don't understand why Ritalin can chil out ADHD-ers yet be sold on the street as an upper.

I think of "stabilizers" and "neuromodulators" as "tendency-toward-teh-mean" drugs (since I'm mathy like that).

Amy, I guarantee you that "sacred, erudite sphincter" is by far the nicest thing anyone has ever said about my anus, and with good reason. For this I commend you and hop to find reason to offer a tribute to your own.

Sorry for the minor hijack, folks, but this is not trivial stuff.

Great. So we're left with Seroquel, Abilify, Haldol, Risperdal, and Thorazine. Being lawsuits and FDA non-approval and laws against chaining my psychotic old farts to the radiators we're screwed.

By Suesquatch (not verified) on 15 Aug 2007 #permalink

Oh, and off-label Depakote.

By Suesquatch (not verified) on 15 Aug 2007 #permalink

Ooh, Oppenheimer's erotic poetry! I learn about something new every day.

Ooh, Oppenheimer's erotic poetry!

This topic may very well deserve its own post on the Refuge.

Thanks for all that info! I downloaded the paper and now I'll be in neuropharm. bliss! =D

One of the interesting twists on this is that many D2 receptors reside on presynaptic terminals that release dopamine, and function in a negative feedback mechanism to regulate dopamine release by those terminals. So a D2 antagonist would be expected to increase dopamine release from dopamine-secreting presynaptic terminals possessing D2 receptors. And a D2 agonist would be expected to decrease release.

By PhysioProf (not verified) on 16 Aug 2007 #permalink

PhysioProf, thanks so much for the well-articulated explanation of dopamine signaling and the effects of antagonists and agonists.* It's almost...erotic. Now I would truly swoon if you expound on retrograde signaling of endocannabinoids!

*A naive question - would a D2 inverse agonist have the same effect as an antagonist?

A D2 antagonist blocks the effect of the native ligand, dopamine. A D2 inverse agonist induces the opposite downstream effect of the native ligand, even in the absence of that ligand.

So, on theoretical grounds, it would seem that an inverse D2 agonist could increase presynaptic dopamine release more than a D2 antagonist, particularly under conditions where release is already low--and thus there is less negative feedback signal for a D2 antagonist to antagonize. I am not familiar enough with the experimental literature in this area to know if this is actually true in practice, or even if it is known.

As I understand it, retrograde synaptic endocannabinoid signaling is a mechanism for a post-synaptic neuron to send information to a pre-synaptic neuron about the post-synaptic neurons level of activity. From an information-processing standpoint, this can be very powerful, as one post-synaptic neuron can have thousands of pre-synaptic terminals on it. So, this retrograde signaling mechanism is a way for the post-synaptic cell to give each of the pre-synaptic cells information about the extent to which its activity is correlated to activity in the post-synaptic cell.

If a particular pre-synaptic cell realizes on the basis of this information that its release of neurotransitter is uncorrelated with post-synaptic activity, it might decide to release more transmitter--i.e., increase its "synaptic strength"--and thereby have a greater influence on the post-synaptic cell. Conversely, if its release of neurotransmitter is exactly correlated to post-synaptic activity, then it might decide to decrease its synaptic strength, so that it has less influence on the post-synaptic cell and thereby allow other pre-synaptic cells to have an influence.

Again, this is a pretty theoretical analysis, as I am not that familiar with the experimental results in this area.

By PhysioProf (not verified) on 17 Aug 2007 #permalink