I Knew Salmon Would Have "More" -- Wired Article Insights, Here

Good to have Salmon back (in comments), even if only for a moment -- in between the Salmon family's end-of-Summer vacation trips -- to give us a much more nuanced look at the Wired Psych Med "Accelerating Placebo Effect" article I first covered last week:

. . . .Ed Scolnick left Merck after a stint as President of Merck Research Labs in 2002 to join the Broad Institute as the head of the psychiatry program -- and to work at the Stanley Center for Psychiaric Research. Stanley is funded by the Danbury Mint Stanleys and founders of NAMI the National Alliance for the Mentally Ill. The Broad Institute is a joint program between Harvard and MIT. This was of course after he arranged for Merck to give a $9 million grant to these institutions.

[Ed. Note: In January 2009, he augmented these posts, apparently looking to cash-in/out on all his knowledge, by joining Clarus Ventures, as a Venture Partner. There, he'll identify promising investment paths for this Cambridge venture capital firm.]

Around the same time Scolnick joined Stanley, his assistant Eve Slater (SVP of Clinical Research and Regulatory Affairs) became Undersecretary at HHS, under Bush 43 -- leaving a year or so later, I believe to join Vertex's Board and take Marcia Angel's place at the NEJM. Then, separately, Merck's VP of Neuro and GI left to go to J&J to develop paliperidone. However, it is interesting that this timing is -- I believe -- about when Vioxx toxicity was first being detected by Dave Graham or slightly before.

MK-869 is a neurokinin 1 (NK-1) antagonist that, in the late 1990s, Merck reported in -- I believe -- Science as having a robust antidepressant effect in a Phase II proof of concept study with minimal side effects. That, in turn, set off a race for a new class of antidepressants. NK receptors were thought to be neuromodulators modulating the effects on things like dopamine and sertonin and people didn't think they would have more than modest effects on any CNS subsystem.

Up until that time, Merck was primarily developing it as an antiemetic for chemotherapy, and although about 15 companies were looking at NK receptor antagonists, no other company had been looking for antidepressant effects -- even though, based on CNS receptor distribution -- it made sense that this might be a possiblity. . . . However, according to my sources, the initial results couldn't be replicated. So the development program was dropped.

It's also interesting that Psych is promoted so heavily by Scolnick in the Wired article because except for MK-869, Merck's CNS research divisions hadn't come up with anything in years -- despite being arguably the most productive CNS program in the industry -- in the distant past. Consequently, the CNS research group (in Canada) was in danger of being shut down.

As for placebo effects, with psych meds, in the past several years, several drugs have shown efficacy in ex-US but not at US sites. That resulted in several drugs being approved -- over FDA reviewer concerns, over this effect.

One possibility is that there is so much overdiagnosis and/or diagnosis of milder forms in the US (and also earlier diagnosis) that perhaps we're not dealing so much with an increase in placebo effect but with a change in study populations as compared to the past (at least in the US).

-- Salmon

August 29, 2009 11:44 pm

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LATER:

. . . .As I mentioned but may not be appreciated it could also be due to earlier diagnosis. As people become more aware of these diseases and become less reticent about revealing them they come in and are diagnosed earlier in the course of the illnesses. This may not allow sufficient cumulative biologic changes that are amenable to treatment to occur but may also shift the population seeking treatment -- so that there aren't as many long term untreated patients available that are likely to respond. This of course is a hypothesis but it might be able to be examined if old data sent to the FDA were made availble (for meta-analysis). This of course would be consistent with FDA white papers promoting such drug/disease data-mining.

Another interesting observation is that the press reported a few months ago that Ed Scolnick testified -- regarding Vioxx -- that he couldn't remember things. This struck me as odd -- Ed Scolnick has a reputation for having a photographic memory. In fact, his subordinates were often afraid to meet with him -- as he would quote back their own data to them, three or four years later.

-- Salmon

Great stuff -- and the idea of over-labeling marginal cases in the US strikes me as a fairly sound explanation for at least some portion of this placebo effect. My sincere thanks, as ever, go to Salmon!