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.

disciplinary medication

Disclaimer: I am not a child psychiatrist and do not speak with professional authority on this subject. These are my own ideas based on various readings and personal experiences.


Everyone loves to hear about someone overcoming obstacles to become a star. This NYT article about Michael Phelps, ADHD-child-turned-Olympian-superstar, caught my eye.

I found most intriguing the bit where Phelps’ mother says that, although he was incapable of sitting still for five minutes in school, he was able to sit patiently at poolside for hours awaiting his chance to swim.

I've heard many stories like this about ADD/ADHD/CD/ODD children: unmanageable under the stringent circumstances of formal schooling (sit still, don't move, don't talk, pay attention), they blossom under circumstances that channel and challenge their natural energy.

In fact, one research team has come up with interesting results suggesting that children with ADHD benefit from exposure to natural settings (Kuo and Taylor).

All this leads me to suspect that this entity which we treat as a disease may actually be a personality trait that lies on the normal spectrum, but that happens to be incompatible with the demands of our technological society.

Human beings evolved to forage, track game, and avoid becoming prey. Those are the tasks for which we were optimally designed. Sitting quietly in school for six to ten hours a day is not in that job description. Humans are amazingly flexible, so most of us can handle it to a greater or lesser degree; but it's not surprising that those out on the high-energy end of the personality spectrum are having some trouble.


So does that mean that we should not diagnose or treat ADHD?  If in another place and time it would have been simply a character trait, does that mean we shouldn't medicate it?  Well, I wouldn’t say that either. Some of the behaviors described for these kids are absolutely beyond the pale of what parents and teachers could be expected to manage by themselves.

Whether these behaviors would be different in a different environment – out on a farm, say, or in a forest – is perhaps irrelevant. We can’t move the kids out of the society they’re in. This is it, for better or worse.

And as always, I’m all for behavioral interventions ahead of pharmacological ones. If the behavior of kids on the milder end of the spectrum can be improved by fixing their diets or letting them tear around outside for a few hours, then that’s an easy decision to make.

But what about kids on the extreme end of the spectrum? The kids who scream, bite, kick, punch, and cannot be coaxed, bribed, threatened, or punished into any semblance of normal behavior?  This is the difficult question faced by parents of ADD/ADHD children: to medicate or not to medicate?

I’m generally extremely wary of giving psychoactive medication to children. The brain is not completely developed until the mid-twenties, and the brains of young children adapt gleefully and abundantly to changing stimuli. If those stimuli include, say, an extended period of dopamine blockade, the brain will adapt by upregulating its sensitivity to dopamine, attempting to restore a more typical balance of dopamine activity.  How long do these effects last? Nobody knows.

Even for the best-studied drugs, there's more information available about gross parameters like height and weight than there is for long-term psychiatric effects.  E.g., Ritalin has been around for a while and is relatively well-studied in children.  At this point it's pretty clear that Ritalin does not have gross effects on children's overall growth and development. I'd be more concerned about subtle long-term changes to their mood and behavior. These things are of course significantly harder to study.  I did find some studies looking at behavior in adult animals who had received psychoactive meds as juveniles.

Here’s a study that shows rats that get Ritalin as adolescents are more sensitive to amphetamines as adults. (Valvassori et al.).  Here's another one that demonstrates the same thing, and also suggests some baseline behavioral changes (Carlezon et al.).  Similar results in this third study (Brandon et al.).

This was later studied in humans and it doesn't look like kids treated with Ritalin are any more likely to become speed addicts as adults than anyone else (less actually), but I'm not aware of any follow-up on, e.g.,  long-term susceptibility to depression or other mental health concerns.

Meanwhile, children are starting to receive medications with much less pediatric data behind them than Ritalin.  For example, the FDA approved the antipsychotic Risperdal for use in children based on three clinical trials that lasted 3, 6, and 8 weeks respectively.

(Risperdal is not approved for use in ADHD specifically but is sometimes prescribed off-label for that indication.)

Huh? Where’s the study that looks at the kids five, ten, or twenty years later? That’s the one I want to see. And barring that (given the difficulties of conducting such extended trials), I’d love to see some more animal studies.

So about those animal studies.  I didn't find many, and what I did find wasn't encouraging. Here’s a study that shows alterations of development, outgrowth, and axonal migration in developing worms receiving antipsychotics (Donohoe et al.).

Unfortunately, the need for behavior control is urgent, and the information just isn’t out there. I think the vast majority of parents are pretty cautious, as they should be, about medicating their kids, and will do so only as a last resort. I also think that’s the right approach; and in the final analysis, if you need it, you need it. Sometimes you have to trade the threat of an unknown outcome in the future for a drop of sanity in the here and now.

But I wouldn’t be soothed into thinking that just because we don’t know about long-term ill effects of childhood medication doesn’t mean they don’t exist. You can only know something is there if you look for it, and that’s something the biomedical research community doesn’t yet appear to have done.