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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

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March 14, 2014

The Genetics of Bipolar Disorder: What A Tangle

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Posted by Derek

Here's a brave attempt to look for genetic markers of bipolar disorder. The authors studied 388 Old Order Amish sufferers, doing thorough SNP analysis on the lot and total sequencing on fifty of them. There were many parent-child relationships in the set, which gave a chance for further discrimination. And the result:

. . .despite the in-depth genomic characterization of this unique, large and multigenerational pedigree from a genetic isolate, there was no convergence of evidence implicating a particular set of risk loci or common pathways. The striking haplotype and locus heterogeneity we observed has profound implications for the design of studies of bipolar and other related disorders.

If you look around the literature, you'll find numerous smaller studies also trying to find genetic markers for bipolar disorder, and many of these propose possible candidate loci. But very few of them seem to agree, and this new study doesn't seem to confirm any of them. The authors hold out some hope for still larger cohorts and more comprehensive sequencing, and that's certainly the way to go. But if there were anything close to a simple genetic sequence for bipolar disorder, it would have been found by now. Like many other diseases (and not just those of the central nervous system), it's probably a phenotype that can be realized by a whole range of mechanisms, an alternate state of physiology that the system can slip into through a combination of genetic and environmental effects. And while there there may not be a thousand ways to get there, there sure aren't just a couple.

Dealing with these "network diseases" is going to keep us busy for quite a while to come. The best hope, as far as I can see, is for less complexity downstream. Maybe these various susceptibilities and tendencies all slide towards a similar disease process which can be modified. Looking back to the genetic causes for understanding sure hasn't worked out so far; maybe advances in studying brain function and patterns of neurotransmission will shed some light. Although if you're having to look to that area to bail you out. . .

Comments (18) + TrackBacks (0) | Category: The Central Nervous System


COMMENTS

1. luysii on March 14, 2014 8:37 AM writes...

Tolstoy got here first -- "Happy families are all alike every unhappy family is unhappy in its own way." This is becoming apparent in just about every psychiatric disease (schizophrenia, depression, mania) and a few non psychiatric ones as well -- autism spectrum disorder (assuming that it is one disease, which it isn't).

What is particularly sad about this paper, is that it deals with a fairly inbred population, the world's best place to look for genetic causes. Since they found nothing, perhaps Tolstoy was not 100% correct. For more see


http://luysii.wordpress.com/2010/07/29/tolstoy-rides-again-autism-spectrum-disorder/

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2. Curious Wavefunction on March 14, 2014 9:30 AM writes...

#1: George Whitesides once applied Tolstoy's quote to drug development in general: Every successful drug has its success in common, unsuccessful drugs are unsuccessful in their own way.

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3. TX raven on March 14, 2014 11:22 AM writes...

The evidence seems to support that these diseases are at a level of complexity hard to understand with current knowledge.
As someone said "if you are digging yourself into a hole, stop digging."

If we wanted to stop doing useless things, perhaps we should discourage using "purely behavioral" in vivo animal models then, and go "100% mechanistic"? Especially for novel targets in CNS diseases...

Just a thought...

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4. vivi on March 14, 2014 1:56 PM writes...

#3: I can't agree more. The DSM (Diagnostic and Statistical Manual, often called "the bible of psychiatry") serves as the ultimate authority for diagnosis, treatment and insurance coverage of mental illness, but a human or rodent brain is too complex to be evaluated and understood by only one handbook.

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5. vivi on March 14, 2014 2:04 PM writes...

"From BALANCE to DSM-5: taking lithium seriously." ← That's what I believe.

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6. matt on March 14, 2014 4:56 PM writes...

@TX raven #3: I may have misunderstood you, but for the vast majority of things in the DSM, "we got nuthin'" on the mechanistic side. If you disallow behavioral descriptions of the problem, then you'll end up having to lump everybody back into "something's not right in the head" and all the stupidity and stigma that entailed. Still entails, in some ways.

If clear mechanistic details emerge, or clearer details of differences in condition emerge, that usually gets put into the next DSM. It's not perfect, but most of the accusations toward it are really aimed at the imperfection of our knowledge. The fix is not to throw away the DSM, but to learn more.

On the topic of the original post, a great many of our prior discoveries in networks of activity come from serendipity (in the presence of sharp observation, followed up by hard work). I'm thinking of things like the Hox gene, where a hugely complex series of events has a simple trigger upstream. But to start unraveling that, someone had to be looking very closely at flies and thinking about genetics and notice a deformity and work out the details.

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7. TX raven on March 14, 2014 5:16 PM writes...

Matt, you are right.
But then again, if nothing changes, we won't be able to continue pissing off billions of dollars in expensive lottery tickets for much longer. Will we?

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8. G on March 15, 2014 10:32 AM writes...

@3: If these disease are at a level of complexity that is hard to understand with our current level of knowledge, then going 100% mechanistic would be like shooting in the dark. We don't know what we are doing. I argue that more behavioral would yield better results that randomly picking a mechanism and then looking for inhibitors/activators. Also, CNS drugs are often very dirty. Perhaps, if things are so complex, then dirtiness can help. Drugs that target a specific mechanism, among the many that likely are involved in the pathology of that CNS disease, may be too specific to be of any good.

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9. TX raven on March 15, 2014 11:00 AM writes...

Dear G @8,
Today, these diseases may be too complex and our mechanistic understanding quite poor too. So, we need to change this situation if we want to go to a better place.

Going "mechanistic" means to me investing in understanding the underlying causes of disease. Say, if we could map in healthy and disease brain what neurotransmitters have changed in what areas of the brain, what circuitries are different and what are the functional consequences of these changes, then we would start attacking these devastating diseases in a more tractable way, IMHO.

Of course, we are talking about a level of investment that only society as a whole can undertake. And we know what the chances are of that happening...

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10. Anonymous on March 15, 2014 7:20 PM writes...

Most common diseases are multifactorial in nature but end in the same phenotype. While it is interesting scientifically to try and understand how all the variety of genetic and environmental factors cause the same disease phenotype, this is not necessary for Drug Discovery.
Understand the phenotype and look for ways to mitigate its effects and you will help patients. Intellectual arrogance leading us to only seek methods that 'cure/reverse' the root causes only show us how little we understand about biology and lead us down pathways where we are unlikely to reap any rewards in our lifetimes.
You only have to look at what has happened in the industry in the last 10 years to see this folly played out.

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11. Anonymous on March 16, 2014 6:21 AM writes...

Perhaps our failure to develop drugs for complex diseases is not due to our lack of understanding, but our assumption that we must understand them in order to develop drugs? So we dig deeper trying to understand something we cannot and do not need to understand, instead of screening lots of random compounds with the right model.

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12. TX raven on March 16, 2014 1:18 PM writes...

@ 11
And how do you decide what the right model is?

@ 10
How do you look for ways to mitigate the phenotype effects if you don't understand their origins? Isn't that what we have been doing the last 10 years?

We seem to agree on the origin of disease, and our poor understanding of disease biology. I am not saying that polypharmacy is wrong or that single target drugs are the only way forward.

Intellectual arrogance? Give me a break...

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13. Anonymous on March 17, 2014 5:48 AM writes...

@12: Prisoners with the disease.

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14. Anonymous on March 17, 2014 6:53 AM writes...

@ 13

You mean them WS fellons?

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15. Cellbio on March 17, 2014 9:34 AM writes...

#9, you make the same argument that has been at the core of drug discovery, cancer research and big biology grant funding (human genome) for the last 20 plus years, depending on the specific area.

While providing a logic which seems plausible, and is for many simpler systems (plumbing), it is a fair debate as to whether the return on molecular mechanisms of disease pathology reward drug discovery.

Your statement that, to paraphrase, once we know what is different then we can start attacking in tractable ways does not adequately reflect that we have limited ability to change what we can measure. Our technology has limits. I am sure much has been measured on the differences in say the autistic brain, but how does one then make those differences go away? Amyloid diseases now have crystal structures, are cures to follow? Sure hope so, and the structures may aide discovery, but the history of mechanistic understanding and targeted therapy has failed to fill pipelines as much as it has filled statements of importance in press releases and grant proposals.

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16. Anonymous on March 17, 2014 11:06 AM writes...

@15: Spot on!

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17. luysii on March 17, 2014 12:39 PM writes...

It's ancient history now (at which I was present), but the purely chemical finding by Hornykiewicz of deficient dopamine in the brain of patients with Parkinsonism, and its correction by giving the precursor L-DOPA by Cotzias, revolutionized the therapy of the disorder. Trust me, the therapy before L-DOPA was released in the USA in '72 was pretty bad. I actually saw patients get out of wheelchairs back then.

So keep looking for disease mechanisms. Here's a more recent example, and one which may make Derek a rich man if it works. https://luysii.wordpress.com/2014/01/27/never-stop-thinking-never-stop-looking-for-an-angle/

Permalink to Comment

18. RL on March 17, 2014 1:02 PM writes...

I have an interesting perspective on this issue, in that I’m a chemist who has Bipolar Type II disorder, meaning I have episodes of major depression interspersed with episodes of hypomania. Starting at age 20, and for the next 20 years, I became depressed on average every two years.
And for the last ten years I have been completely stable due to taking Lamictal (lamotrigine), experiencing neither extremes of the disease. I understand this drug was first developed to treat epilepsy, and then was approved to treat bipolar disorder. However the drug works, it’s supplying the missing ingredient (or ingredients, or balance of neurotransmitters) that is a lifesaver for me.
There is definitely a genetic component to my illness. I have a maternal uncle with the same illness, though interestingly, neither my parents or brothers have the disease. My uncle also has a similar personality to me – he’s an introvert who loves to read, and has very strong interests in his hobbies, and who did well in school, unlike all of his immediate family. Oddly enough, neither of his two children has the disease or is an introvert.
And psychiatrists, who I am obligated to deal with, seem to only have the haziest of understanding of medications and how they work. I think the grand majority of them operate in some kind of black box. I once had to explain to the Lamictal-prescribing one that there was no point in taking the controlled-release version since the regular version is only taken once a day, with a half-life of 24 hours. She thought ‘half-life’ meant the time it takes for the blood concentration to go to zero. I explain that the ‘half’ designation means ‘half the initial concentration’.
But she wasn’t the worst of the bunch. My first psychiatrist insisted that my recurrent depressions were due to the ‘tragedies’ in my life. He prescribed four weekly visits for psychoanalysis. I politely declined.

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