There was a pretty awesome science breakthrough yesterday on the genetic and physiological roots of schizophrenia.
The most strongly associated markers in several large case/control cohorts were near a complex, multi-allelic, and only partially characterized form of genome variation that affects the C4 gene encoding complement component 4 (Extended Data Fig. 1) . The association of schizophrenia to CSMD1 (refs 6, 10), which encodes a regulator of C4 (ref. 13), further motivated us to consider C4….
The association of schizophrenia to these genetic variants exhibited two prominent features (Fig. 4a, b). One feature involved a large set of similarly associating SNPs spanning 2 Mb across the distal end of the extended MHC region (we use this set’s most strongly associating SNP, rs13194504, as its genetic proxy). The other peak of association centred at C4, where schizophrenia associated most strongly with the genetic predictor of C4A expression levels (P = 3.6 × 10−24) (Fig. 4a and Extended Data Fig. 5). In the region near C4 (chromosome 6, 31–33 Mb), the more strongly a SNP correlated with predicted C4A expression, the more strongly it associated with schizophrenia (Fig. 4b, bottom panel)…..
What this research means is that scientists are isolating a probable cause for at least some forms of schizophrenia. A specific gene variant causes some immune systems to ineffectively prune neurons during the transition from late teens to early adulthood.
This is amazing. It gives bio-chemists, neurologists, doctors and drugmakers a fairly precise target to chase for new drugs. The best case scenario is for those drugs that have yet to be invented will be available for prescription in eight to ten years. The probable case is much longer.
However there are several things that a best case scenario illustrates for discussion purposes:
- How much should a drug cost?
- Who should get them?
- Who pays?
Schizophrenia is an expensive condition to treat. On average, schizophrenia costs $10,000 or more per person per year in direct medical costs. Indirect costs are higher. Treatment right now is harm mitigation, psychosis minimization, and behavioral modifications. If there was to be a cure or a significant prophylactic treatment that significantly reduced symptoms it would be a game changer.
Let’s assume a wonder drug that has a high probability over a course of a single treatment regime of indeterminate time where the end result is a very significant reduction in the number of people who are diagnosable at the end of the treatment and observation regime with schizophrenia. How does that wonder drug get priced?
Assuming a fifty year life after initial diagnosis and initial treatment cost of $10,000 per year, the lifetime incremental net present value of treatment cost can vary between $480,000 (3.5% medical inflation rate, 3.5% discount rate) to $900,000 (6% medical inflation rate, 3.5% discount) to $1.2 million dollars (6% medical inflation 2.5% discount rate). These assumptions are highly sensitive to initial assumptions, but over the course of a lifetime, any assumption produces a fairly large incremental cost to treat.
Under a basic analysis of market forces, the wonder drug would be priced at a smidgen below current cost of treating schizophrenia with a discount equal to the failure rate of the wonder drug. This schema could produce pricing of $300,000 or $500,000 for a prophylactic regimen given to teenagers who had the bad version of the pruning gene.
The argument would be that the regimen brought forward the very long run costs and avoided them, so the economic value over the life of the individual being treated to avoid a serious mental illness should be encapsulated with a minor discount for the new technology as it saves the system money over the very long term. This is basically the argument that has been used when Solvaldi was introduced. Hep-C had lifetime treatment costs above $100,000 per individual, so a pill at $85,000 that produced a cure was a “good deal”. Since then, competition by similar drugs with similar results have driven down the actual prices paid for the new Hep-C cures.
That argument may be valid, but it would be an argument that bankrupts every single insurer in the country and most states’ Medicaid and CHIP programs in the first year. It would be a replication of the Hep-C cost crisis times a thousand.
Instead the payers would do two things. The first would be to use public pressure initially and then competition among near substitutes in an attempt to drive the cost of the drugs down to the combined cost of R&D plus manufacturing/administration. Secondly, the payers would be looking at massive up front costs if they treated everyone. They would try not to treat everyone. They would treat people who had the highest probability of becoming schizophrenic. People would be assigned a risk score based on some set of criteria and only the people in the top tiers(s) would get the very expensive drug as that is where the greatest bang for the buck would lie. The goal would be to treat the worst off and most probably the most expensive over the course of the lifetime while hoping that the non-treated but eligible for treatment individuals can muddle through long enough for prices to come down.
And that raises the question of who pays? There is a good argument that the federal government could and should finance a very large public health campaign to reduce Hep-C to a small, localized disease through funding very aggressive pharmaceutical treatment to reduce the carrier pool and needle exchange to reduce the odds of infection transmission among non-treated carriers and frequent testing among high risk populations and less frequent testing among all populations. A single large public health pulse over several years would knock Hep-C back significantly. Knocking back an infectious disease produces very large gains through cost aversion in the out years. Schizophrenia is different as there is always a new cohort of people who are entering the high risk years of teenage and early adulthood neurological pruning. Treating a member in a network at high risk does not change the risk of symptom manifestation of other people in that network unlike in the Hep-C example.
A single pulse would not solve the problem. It would improve the lives of many people who are touched by that pulse but five years later the next cohort would face the same risk profile no matter how successful the previous pulse was.
There can be a good argument that the federal government should take on the costs of prophylactic treatment of individuals with high risk genetic markers. The feds could use their purchasing power to get a good deal among a set of near substitutes to reduce overall costs. Furthermore, the federal government can afford to wait thirty years for pay-offs as the population does not churn. Private insurers would gladly hand off the risk and the costs as they know that if they treat a 16 year old, they won’t see the reduced future costs as that 16 year old will have moved to Nashville to start a bad band at age 21 and then goes to work for a medium size financial service firm in Denver at age 32. If a treatment like this was to be paid for with private insurance, the Exchanges would be better able to handle this type of shock as there is back end risk adjustment so insurers would not run from these risks. Group insurance would not have risk adjustment so insurers would run like hell if they can.
This is a tough example and it deserves some thought as to how a drug or treatment regime would be treated.
I love your analyses of these “good news, but…” situations. The issues are always more subtle than they appear to me at first glance. If you’re still thinking about (or writing) a book, I hope it has the flavor of “Here’s how to think about these situations.”
One of my disabled clients that I job coached last year had schizophrenia. The drugs that allowed her to function without hallucinations were so strong that carrying on a conversation took great effort on her part, her hands always shook, and her affect otherwise was so flat she could have been mistaken for a zombie. Anything that promises hope of a better treatment for that disease would be a god-send, because right now the treatments are themselves somewhat disabling.
Just to point out the obvious, this isn’t a tough example at all in a socialized medicine environment. The costs of the treatment itself are dwarfed by the overall loss of productivity on a per capita basis, and the gubmint has just as much skin in the game as the individual in such an environment.
And the $ costs are nothing compared to the social/emotional quality of life costs. Watching otherwise smart, well-related and forward looking adolescents slide into the abyss is horrifying. Being one of them is even worse.
@dr. bloor: I saw my cousin go that way and the kid I remember still pops out every now and then but yeah, this is terrifying — it is one of those things I watch as there is a strong family history on my mother’s side for a variety of manifestations of schizophrenia. It skipped my generation, but who knows if I carry that particular mutation and passed it to my kids…
As a side note, I remember reading somewhere that autism’s observable onset in preschoolers happens at a time of great brain re-organizing… any chance that something similar could be at play where things get pruned differently?
@Richard Mayhew: Yep. I don’t follow the basic neuroscience all that closely, but they’ve been looking at this for a while now.
Getting from the basic neuropathology to a cure, however…
@dr. bloor: agreed, best case scenario mid 2020’s probable case scenario way longer
Plausible case scenario — never
Shit, paywall. Would love to read the whole thing.
Schizophrenia is one of those diseases that wreaks havoc not just on the victim, but pretty anyone who comes in contact with that person. Lot more costs than meet the eye. This would be great if even preventable, much less curable (if the disease mechanism is as stated and literal brain damage is involved, I don’t see how that gets cured).
@Richard Mayhew: I’m an autism mom and I can tell you my son’s difference was immediately noticeable. As a newborn, he started smiling right on schedule but only off into space — never AT anyone. It was a smile but it wasn’t a “social smile.”
That said, there are many different autisms, they just have not been clearly differentiated yet (and I don’t think the new DSM approach of lumping everything together is going to help any efforts to tease apart the many kinds of autisms).
So it very well might be that one or more variations of autism ARE a result of unusual pruning.
As for scientists claiming any results will be as soon as ten years: ten years is their favorite number. It’s *always* ten years. My freshmen philosophy professor was married to a geneticist and that was what he told us, and I have seen that confirmed again and again. It must be an inside joke a mong scientists.
I follow neuroscience pretty closely (PhD and all) and while this is great in terms of knowledge it is (probably) not great news on the treatment front. This suggests that schizophrenia is basically a late neurodevelopmental disorder (like autism but occurring later?), which is really not amenable to the kind of small molecule treatment that drug companies can address..
That said, identifying the genes/physiology and developing mouse models does allow testing of small molecules on symptoms caused by specific genetic backgrounds, which is a lot better than nothing, but far from any sort of “cure”. And as Ohio Mom says, correctly, there are many variations of all these diseases. There are likely dozens of different versions of autism, schizophrenia, dementia, etc., which is why I tend to be more optimistic about using these genetic findings to develop models for treatment of specific symptoms than any type of “cure”.
But none of this is likely to help in the next 10 years (FWIW, NIH has gotten impatient lately, so 5 yrs is the new 10!! So now we’re deluding ourselves twice as much!!)
@Ohio Mom: I thought it was 30 years for commercially viable fusion not 10 :)
My mother is a paranoid schizophrenic. I knew something was wrong when I was growing up, but I did not learn until very late in life her diagnosis and that she was thirty years old (the year of my birth) at its onset. Paranoid schizophrenia for her, destruction of the lives of her four children, and every other family relationship as well. I am a member of a club that I never wanted to be a part of.
My mother will never benefit from a cure, and her condition is well controlled by the new generation of antipsychotics, but my God! to hear of this breakthrough is a really wonderful thing. Hope! Light in the midst of darkness! If not for my family, but for others.
@Richard Mayhew: Just an example of Physicists being smarter than Biologists, in 30 years no one will remember your prediction or expect results! Of course, if you tell people that you’ll cure XXX in 30 years, their eyes will glaze over and they’ll tell you it’s moot to them (generally). So maybe it’s just that the smartest choose Physics over Biology…
@Xanthippe: I have a good friend who is also the child of a paranoid schizophrenic so I have witnessed a bit how the ensuing dysfunction spreads. There are a couple of great-grandchildren whose lives are messes because their mom’s (friend’s niece) was a mess because her mom (friend’s sister) was a mess because of her mom’s (friend’s mother) schizophrenia. It’s been a huge effort on my friend’s part to right the ship of her own life and raise her kids without transmitting the trauma.
Maybe there is something to that biblical pronouncement about the sins of the father going on for generations, using a very wide definition of “sin.”
Ohio Mom, et al. I know that autism, schizophrenia, depression, bipolar and ADHD all have a genetic linkage. The study was looking for what the genetic difference was, because these can be overlapping diagnoses. I took a psychology course on how we define disorders, focused on ADHD. One of the fascinating theories, which I can feel strongly through my ADHD, is that these are disorders based in faulty time perception.
I had a classmate who seemed fine at prom, but wandered off in a hallucination during final exams and was in a locked ward while we graduated. Horrible, horrible.
On the money side of things – one of the problems with the estimated cost benefits is what if someone needs more than one of these treatments? Or is paying off the student loan which captured a fairly large portion of their future earnings, only to then require a biologic?