Wednesday, November 12, 2008

a science in need of a theory

I've had a number of people wonder why, as someone with a research background, I'd be interested in psychiatry. There's a tendency to view psychiatry as 'fluffy' and not something that would be interesting to a person who has spent years getting down and dirty with cells and proteins.

In my view, psychiatry is truly biomedicine’s last frontier, and no medical specialty could be more fascinating for someone who loves unanswered questions.

Medical science can speak knowledgeably on a molecular and tissue levelabout the causes of diabetes, asthma, and cardiovascular disease. We can trace Type I diabetes from the death of a specific cell type (pancreatic beta-cells) through the loss of their hormone product (insulin) to the immediate result (inability to use and store food energy) to the final result (death, before insulin was widely and cheaply available). We could tell you another good story about heart disease: fatty deposits build up inside the arteries that feed the heart, narrowing their cavities until they can be clogged by small bits of clotted debris, starving the heart of blood and resulting in the death of its muscle tissue - a heart attack. (Yes neither story is so simple, in a nod to the endocrinologists and cardiologists out there - but let's not get bogged down in details.)

However, the DSM-IV lists not one disease for which such a clear pathophysiological chain of events has been established. When faced with depression or schizophrenia, medical science begins to wave its hands, to stutter and mumble vaguely about deficits or excesses of this or that neurotransmitter. In this sense, psychiatry is truly biomedicine’s last frontier.

Sure, we have some vague hypotheses about things. Take for example the 'dopamine hypothesis' of schizophrenia. That's the hypothesis that schizophrenic patients have too much dopamine in the frontal cortex (resulting in positive symptoms like hallucinations and delusions) and not enough in the subcortical areas (resulting in negative symptoms like social isolation and flattened affect). That explains why dopamine-blocking drugs improve the positive symptoms but aren't so great at fixing the negative ones.

That's a nice finding, and it is likely accurate to a degree; but it's not what you would call pathophysiology. That's like saying the problem with my computer is that it's got too much electricity in the hard drive and not enough in the disk drive. The computer doesn't work by bathing its various parts in electricity, and neither does the brain work by bathing its various parts in neurotransmitter soup. The important thing for each of them is the patterns in which the circuits are communicating with each other, and naming the medium of that communication - be it electricity or dopamine - isn't anything like the answer to a question about why the system is broken.

But nonetheless, psychiatry continues to offer explanations like "Too much dopamine!" or "Not enough serotonin!" to questions about why people have various psychiatric illnesses.

Many of these answers are based on reverse-engineering from medication effects. We've got this drug that increases serotonin transmission, and it fixes depression, so therefore depression must be the result of insufficient serotonin. We've got this other drug that blocks dopamine transmission, and it fixes schizophrenia, so therefore schizophrenia must be the result of too much dopamine.

The obvious problem with this reasoning is that a drug isn't a perfect reversal of a disease process. A disease has some complex effects, and a drug has some other complex effects, and some of the drug effects work to cancel out some of the disease effects, but the overlap is in no way perfect and doesn't necessarily offer us any information about the root cause of the disease.

When John Snow removed the handle of the Broad Street pump to halt the 1854 cholera epidemic in London, did that mean that working the pump handle gives a person the cholera? No, and neither does 'fixing' your depression with more serotonin mean that depression is ultimately caused by 'not enough serotonin.' Serotonin is playing a role in there somewhere but a 'serotonin deficit' is overly simplistic as a cause of anything so complex as a psychiatric disorder.

So the drugs do a bunch of things, and symptom relief is only part of the picture. I don't really think they're fixing whatever the underlying problem is, only pushing the brain into a more manageable state (not quite a normal one). Although some schizophrenics are quite pleasant and normal when they're appropriately medicated, lots of others are still evidently off.

So what would a theory of psychiatric disease look like - a real one? Don't look at me, I'm just the critic. But this very interesting and timely article in the New York Times describes a couple of authors who have developed something that's much more along the lines of a Good Theory than any of the other vagueness I've heard. I'm not certain I agree with their lumping of psychosis and mood disorders as fundamentally similar, but I like the way they think.


Neuroskeptic said...

Hey - a very interesting post. Although I think you got your PFC and your Ventral Striatum mixed up - current orthodoxy is that dopamine is increased in the latter and decreased in the former, in schizophrenia. Although as you go on to say, that's about as vague as it's possible to be.

I wrote a post on a similar topic, although focusing on depression : here

What's fascinating to me is that all the evidence we have suggests that something really interesting is going on with serotonin and depression (and dopamine and schizophrenia, etc.) but we don't know what it is yet. A final frontier indeed...

schlockdoc said...

Thanks for the edit - I should have checked before posting. Nice blog too btw.

Dr. Deb said...

The better technology gets and the more we learn about neurochemistry and the brain, then we will be able to make our soft science more empirically based. But I get what you're saying.