Monday, March 30, 2009

Figuring Out Schizophrenia

I'm back home after an exhilarating and exhausting day at the International Congress on Schizophrenia Research in San Diego, 40 miles "down the hill" from where I live. To briefly recap:

Early morning: I'm up at 5 AM and out the door an hour later. Shortly after seven, I announce myself to a small breakfast gathering of brain researchers as, "The only C student at this table."

The line works so well I use it the rest of the day. It doesn't take me long to get into the spirit of the conference. I start referring to my coffee as my "neuro-cognitive starter." I find myself talking to a woman who is not a brain scientist. Her doctorate is in education, and she is involved in changing behavior in patients that just about everyone else has given up on.

"You can change the brain by changing behavior," she lets me know. Little steps at a time. You will probably hearing a lot more about her, if for no other reason than I plan to be writing more about her.

Late morning: I arrive at my appointed symposium for two hours of dopamine. These are brain scientists talking to brain scientists. To give you some perspective: When brain scientists talk to psychiatrists, they dumb down their talks. That way, I can almost understand their presentations.

Not the case here. Daniel Weinberger of the NIMH is one of the presenters. A couple of years ago, at the American Psychiatric Association annual meeting, I heard him explain to his audience the val-met COMT variation. Today, he just assumes that the people in the audience understood. Then he gets really technical.

Just over the aisle, in the same row where I am sitting is Arvid Carlsson, recipient of the 2000 Nobel Prize in Medicine (with Paul Greengard and Eric Kandel). Dr Carlsson received his Nobel for his work into dopamine. Let's put it this way: BC (Before Carlsson), dopamine had minor chemical status. Then Dr Carlsson started investigating and suddenly dopamine was a major neurotransmitter. (That's Dr Carlsson's photo to this blog post.)

In order to appreciate the environment Dr Carlsson was working in at the time, science only had theories about how brain cells communicated. Chemical? Electrical? Dr Carlsson and his contemporaries resolved that debate, but not without bucking a lot of the conventional wisdom of the day. In addition, Dr Carlsson connected dopamine deficiency to Parkinson's, which in turn led to L-DOPA for treating the illness, thus benefiting untold millions.

So here's Dr Carlsson listening to a younger generation of scientists carry on his work. Immediately after the session, I walk over and ask for his autograph. (I was a C student, remember? I can get away with this behavior.) He graciously signs the inside back cover of my conference booklet. My son-in-law is a neurosurgeon in New Zealand and a great guy. He's gonna be thrilled when this autograph arrives in the mail.

Don't tell - it's a surprise.

Early afternoon: Over lunch and at the poster session, I get to talk to the researchers one on one. First, let me make a confession - the technical stuff is way over my head. I'm here to simply get a feel for things, develop an appreciation. One of the things I notice is that the posters on the cognitive aspects of schizophrenia outnumber the psychosis side of the illness by a ratio of at least three to one.

Was it this way ten years ago? I wonder. I'll have to ask. Antipsychotics work very well against psychosis, but when your basic thinking is messed up - never mind the psychosis - your life is going to involve smoking cigarettes in front of TV in some dreary day room someplace.

No wonder the people I'm talking to are telling me that doctors and patients and family members got oversold on the new generation of antipsychotics. From what I can gather, certain systems in the brain go down. Systems we are only just finding out about. Systems we haven't even discovered yet. Systems all over the brain, interdependent, so when one system goes down, different parts of the brain all over fail to talk to one another.

Some of it is genetic. Some of the genetic mischief occurs during fetal development, other mischief further on in the life span. There may be direct genetic impact, or it may be like billiard balls caroming off one another. Or it may have something to do with a new area of gene research called epigenetics (which has something to do with why identical twins aren't really identical).

And forget about finding schizophrenia genes. These guys seem to be concentrating on "endophenotypes," symptoms common to the general population, as well, say, delayed reaction time to an event. If, say, we find a delayed reaction time gene and connect it to neurons and connect the neurons to brain systems and connect the brain systems to behavior, and connect the behavior to schizophrenia, maybe then we can really start connecting some dots.

Then there's environmental factors. The brain is shaped by literally everything, such as the way a mother holds her baby. African-Caribbean immigrants in the UK, for instance, have a nine-fold higher schizophrenia risk than the rest of the population there. What is going on?

Later afternoon: My brain is on overload. I leave the conference at four and am home at five. Twenty minutes later, I'm crashing in my own bed.

Evening: Dinner, chill time, and this blog post. Time to kick the cat off the prime spot on my bed. Up at five again tomorrow. I love my job ...


Tony said...

I think it is wise to try to keep up with research on schizophrenia since a recent Swedish study in The Lancet demonstrated that bipolar disorder and schizophrenia somehow share the same genes. That would explain why the same medicines work for both. The complexity of how the glutamate system (which lithium works on) and the dopamine system (which the antipsychotics work on) interacts is interesting. Both are implicated in both diseases. I would be curious how researchers are thinking about treating the negative symptoms of schizophrenia and how those might help alleviate the cognitive deficits seen in bipolar disorder. Using the literature resources available at work, the only thing I came across was a very small study of patients with schizophrenia on clozapine being treated with methylphenidate to see if the latter would alleviate the negative symptoms. The results were fairly positive. But that was a few years old, I would be curious to see what they have investigated since then.

There is a drug Eli Lilly has in clinical trials which is an agonist of the muGlu2/3 receptor for treating schizophrenia. (An early study showed promise, but a recent study had an unusually large placebo response that trumped the new drug. Lilly is going to try again.) I wonder when they will try this drug for bipolar disorder since it works on the glutamate system, one of the targets of lithium.

All very interesting. Thanks. Keep us posted.

-Tony (aka cretin)

John McManamy said...

Hi, Tony, There's an article on my mcmanweb site about "DARPP-32," which has a large part to do with the interface between the glutamate and dopamine systems. Paul Greengard shared his Nobel with Arvid Carlsson for his work in this area (Eric Kandel also shared the Nobel). I heard Dr Greengard at the APA in New York in 2004. I could barely understand a word, but I can assure you the talk motivated me to find out a lot more.

Re the muGlu2/3 receptor med. This comes from John Krystal's work. Two years ago, at the APA in San Diego, I heard Dr Krystal. For some reason, I never uploaded the Newsletter version of this report to my mcmanweb website. Maybe at the time I didn't see the bipolar-depression connection. I'll have to correct the oversight.

As you point out, there is obviously a BP connection to the muGlu compound. Out mood stabilizers work on the glutamate-GABA tag team. Clearly, the compound needs to be investigated for BP.

Anyway, many thanks for your input and very glad you appreciate these articles. I love reporting on the brain science.