The New York Times today ran a piece on the disappointments encountered by geneticists, recently -- in identifying causes of common diseases, through study of the afflicted patients' genetic code. It truly is a fabulous piece of reporting -- do go read it all. I'll wait.
And so, I was doubly delighted to find that the Times also ran a companion editorial (by Nicholas Wade -- do go read it, from top to bottom, as well!), which literally took my breath away, with the grace and precision of its delivery:
. . . .It seems to me the reports represent more of a historic defeat, a Pearl Harbor of schizophrenia research.
The defeat points solely to the daunting nature of the adversary, not to any failing on the part of the researchers, who were using the most advanced tools available. Still, who is helped by dressing up a severely disappointing setback as a "major step forward"?. . .nature is often a lot more complex than assumed. It now seems that the arm of natural selection is far longer than thought. It has reached way beyond our reproductive years and zapped most harmful genetic variants before they could get to be common in the population. That leaves relatively uncommon variants, lots and lots of them in each case, as the genetic cause of each common disease.
In the last few years gene hunters in one common disease after another have turned up a few causative variant genes, after vast effort, but the variants generally account for a small percentage of the overall burden of illness. With most common diseases, it turns out, the disease is caused not by ten very common variant genes but by 10,000 relatively rare ones.
Today it’s the turn of schizophrenia researchers to make the same discovery. . . .
Schizophrenia too seems to be not a single disease, but the end point of 10,000 different disruptions to the delicate architecture of the human brain. . . .
So the press release writers could have cast it as a noble defeat, were words like defeat a part of their vocabulary, or frankness their masters’ priority. . . .
So -- why asenapine (the chemical name of the drug Hassan proposes to brand as "Saphris", in the United States), that decidedly old-schoolish Schering-Plough candidate awaiting an FDA decision, later this year (rescheduled from the middle of last year) for treatment of schizophrenia? Because we now know several other large pharma players passed on bringing it to market, before Fred Hassan threw perhaps a half-billion dollars into trying to get it approved -- at Schering -- for schizophrenia.Yes, the "defeat points in some measure to the daunting nature of the adversary" -- and, in the case of asenapine, perhaps even more to the hubris that leads one CEO to think he could succeed where scores of others have assessed (including Pfizer, quite rightly, it seems) that it wouldn't be "a major advance".
4 comments:
The unfortunate part to much of health research is that scientists still pursue their efforts along the path of the 'magic bullet' mentality. This is driven by both the scientists and the business people. In order to get funding from the 'accountants', scientists must explain the ulitmate findings of their work as a cure all. In order to get the backing from investors, the company must sell the pipeline the same way. If not, no-one wants to support the project. This also drives the machinery for 'me too' drugs. Go with a winner when you have structural analogs.
As a nation, we need to accept that research on health often are 'information gathering' exercises. That as we learn more, we may be able to help more. But, there are no guarantees. However, since many of our schools districts are still trying to teach Creationalism, it doesn't seem likely.
Very-well put, Anonymous! Thanks for your insights -- with which I agree 100 percent, by the way.
Especially the unfortunate truths about much corpoate sponsored drug, and biologicals research-funding process dynamics -- and the part about some teachers trying to classify "natural selection" as a form of religious study -- not science -- to give creationism so-called "equal footing", in the classrooms of public schools.
Preposterous.
The results are not surprising.
First schizophrenia (skee-zo-fren-i-a not skit -zo-fren-i-ais) is most likely not a single disease we've thought of it in this manner for decades based on the symptoms. A large fraction become paranoid and withdrawn, others are happy and just laugh at everything, most have auditory hallucinations and others visual, other symptoms such as thought problems, verbal communication, and breakdown in knowing personal space can vary significantly.
As a clinician it's extremely difficult to try to figure out from external observations and discussion what even the symptoms are and what type of mental illness we are dealing with. This is particularly true for children and the changes in symptoms that occur over time.
The brain is the most complex organ in the entire body it controls thought, emotion, memory, and movement. The types of cells and the complexity of the interconnections, the intercellular biochemical actions. and what the can do is simply staggering and we essentially understand very little about how normal brains work much less diseased ones.
As for genetic causes this is not suprising. Cystic Fibrosis was the first genetic disease tackled and it was due to a defect in a single gene product a chloride transporter. Yet soon (1-2 years) after discovering the target it was apparent that there well over 1000 mutations with different degrees of effect on function from extremely severe disease resulting in death in childhood to mild illness that might otherwise not be detected but might explain a greater propensity for say respiratory infections. Plus poorly functioning chloride channels resulted in compensatory activity by other channels and that likely led to some of the problems.
The complexity of the brain makes the likelihood that schizophrenia is due to defects in multiple possible brain activities from interconnections to receptor number and binding, to intracellular downstream effects on mitochondria highly probable.
Examining the drugs that we use it's clear that they are extremely dirty and hit multiple multiple receptor targets and act in many different ways. Plus the extensive metabolism with alterations in receptor binding and effects with differences in metabolite and enantiomer exposures make it likely that you are going to have effects and side effects that you don't anticipate or understand.
On top of all this we need to remember that nature uses these same basic building blocks over and over and varies them via mutations. So it is not surprising that we have effects on the heart or the liver, or kidney's, or muscles. Or if the drugs effect mitochondria or some other target that there is cumulative toxicities that occur after years at related sites (such as the pancreas where they may cause cell death and diabetes) or on the brain itself.
Considering all this it's amazing that we have drugs that work at all. However you have to realize that a drug may work extremely well in a amall percentag of people and drive the average improvements in scores that we use to measure efficacy but in the majority work no better than placebo and in another fraction may actually make mental illness worse, (e.g. suicide, psychosis, violence). Even that idea that short term efficacy or even moderate term (6 months - 1 year) will predict long term efficacy and safety is suspect and in fact evidence from other countries tend to support this.
When you consider all this and look at how psychiatry is practiced with little to no thought or self questioning of assumptions and what happens to patients it's no wonder that patients feel victimized and many claim there are no such diseases or biological basis.
As my boss used to say when I worked in this area 'this isn't rocket science. Rocket science is easy!."
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We need to listen to our patients. I was at the last psychopharmacologic drug advisory committee meeting and the patient representative was a mother whose son committed suicide and when I and other heard the story thought it was suspicious for drug induced suicide. Instead she stated that patients would rather be on the drugs and have clear thoughts and deal with the side effects. That is simply false. Many patients will accept a lower less effective dose but not a higher more effective one due to side effects. Others prefer to not take drugs at all and know that they're acting strange to others but they've made a decision and when you speak to them you realize in spite of the mental illness that it's an informed one. Instead you have families and drug companies funding campaigns to forcibly medicate people even when they're not dangerous. Plus even forcibly administering these drugs to any kid who goes into foster care or an instituion and other kids when they aren't indicated on the hypothesis that they will prevent illness when in fact with all the effects it's most likely that they will be causing problems and even death well before they might truly need an antipsychotic.
As for asenapine if it worked well I assume that it would have been approved long ago (of course there are ways to rig the system even when the studies fail and you can't tell if a drug works or not).
Thus the most likely reason for the long development, Pfizer dropping it, and the delays in approval are most likely major toxicities. Considering the major toxicities we're seeing with the structurally similar antipsychotics (Clozapine - agranulocytosis and cardiac effects, Zyprexa - cardiac effects and diabetes, Seroquel - the same) We can only surmise that the magnitude and severity of the toxicities with asenapine must be truly horrific. Of course perhaps this is why it's only submitted for short term use even though no one would ever prescribe an antipsychotic for only short term use.
Rather than hubris where Pfizer and other failed, perhaps Fred is simply doing what he has done before. Moved on before the s--- hits the fan and sold the company to someone else to deal with the mess. So I wouldn't be surprised if Merck is simply taking on another Vioxx. But this time rather than treating people at the end of life who may be able to accept the risk for themselves for a true possibility of benefit. We are instead forcibly or tricking people into medicating children without schizophrenia or clear bipolar disorder with symptoms that part of every study where response has been shown, so there is no evidence of any benefit in the majority of the children treated and clear evidence of serious harm and death.
Salmon
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