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Saturday, January 9, 2010

A Decade for Psychiatric Disorders...?

Nature kicks off the 2010s with an editorial pep-talk for psychiatry: A decade for psychiatric disorders.
New techniques — genome-wide association studies, imaging and the optical manipulation of neural circuits — are ushering in an era in which the neural circuitry underlying cognitive dysfunctions, for example, will be delineated... Whether for schizophrenia, depression, autism or any other psychiatric disorders, it is clear... that understanding of these conditions is entering a scientific phase more penetratingly insightful than has hitherto been possible.
But I don't feel too peppy.

The 2010s is not the decade for psychiatric disorders. Clinically, that decade was the 1950s. The 50s was when the first generation of psychiatric drugs were discovered - neuroleptics for psychosis (1952), MAOis (1952) and tricyclics (1957) for depression, and lithium for mania (1949, although it took a while to catch on).

Since then, there have been plenty of new drugs invented, but not a single one has proven more effective than those available in 1959. New antidepressants like Prozac are safer in overdose, and have milder side effects, than older ones. New "atypical" antipsychotics have different side effects to older ones. But they work no better. Compared to lithium, newer "mood stabilizers" probably aren't even as good. (The only exception is clozapine, a powerful antipsychotic, but dangerous side-effects limit its use.)

Scientifically, the 1960s were the decade of psychiatry. We learned that antipsychotics block dopamine receptors in the brain, and that antidepressants inhibit the reuptake or breakdown of monoamines: noradrenaline and serotonin. So it was natural, if unimaginative, to hypothesise that psychosis is caused by "too much dopamine", and that depression is a case of "not enough monoamines". (As for lithium, we still don't know how it works. Two out of three ain't bad.)

These are still the core dogmas of biological psychiatry. Since the 60s, the amount of money and people involved in the field has exploded, but today's research is still essentially making footnotes to the work done 30 or 40 years ago. It would be somewhat unfair to say that we haven't made any solid advances since then, but only somewhat.

The double helix structure of DNA was discovered in 1953, just after antipsychotics and antidepressants. Imagine if biologists had learned about the double helix, but instead of using it to understand genetics, or catch criminals, or sequence genomes, they spent 50 years arguing about whether all DNA was shaped like that, or only some of it.

The standard response to the charge that psychiatry has lagged behind the rest of medicine is that "It's hard". And it is, because it's about human life, which is complex. But so is the subject matter of every science: the whole point is to seek simplicity in the complexity. Genetics was hard, until we worked out how to do it.

What's remarkable is that so many things in psychiatry are simple. For example: any drug which blocks the dopamine transporter (DAT) in the brain has stimulant effects: increased energy, focus, and motivation, and at high doses, euphoria, grandiosity, and potentially addiction. Cocaine, amphetamine, Ritalin etc all work this way. There are no cocaine-like drugs that don't block DAT and no DAT inhibitors that aren't cocaine-like. Simple. The stimulant high looks strikingly like the mania seen in bipolar disorder, and is pretty much the exact opposite of what happens in clinical depression. Couldn't be easier.

There are plenty of cases just like this. What's also striking is that neuroscience has advanced in leaps and bounds since the 1960s. A 60s, or even a 90s, textbook about neuroscience looks incredibly dated - a 60s psychiatry textbook is essentially still up-to-date except for the drug names. Contemporary neuroscience is far from being a mature science like genetics, it has its problems (see: all my previous posts) but compared to psychiatry, "basic" neuroscience is rock-solid. Although I trained as basic neuroscientist, so I would say that.

Why? That's an excellent question. But if you ask me, and judging by the academic literature I'm not alone, the answer is: diagnosis. The weak link in psychiatry research is the diagnoses we are forced to use: "major depressive disorder", "schizophrenia", etc.

Basic neuroscientists don't use these. If a neuroscientist wants to study the effect of, say, pepperoni pizza on the human caudate nucleus, they can order a Dominos, recruit their friends as research subjects, pop them in an MRI scanner and get to work doing rigorous (and delicious) science. They've got the pepperoni pizza, they've got the human caudate nucleus - away they go.

Whereas in order to do research in psychiatry, you need patients, and to decide who's a patient and who isn't you basically have to use DSM-IV criteria, which are all but meaningless in most cases. It doesn't matter what amazing new scientific tools you have - genome-wide association studies, proteomics, brain imaging, whatever. If you're using them to study differences between "depressed people" and "normal people", and your "depressed people" are a mix of people who aren't ill and just need a holiday or a divorce, undiagnosed thyroid cases, local bums lying about being depressed to get paid for being in the study, and (if you're lucky) a few "really" clinically depressed people, you'll not get very far.

Edit 10.1.2009 - Changed the date of the discovery of the structure of DNA from 1952 to the correct 1953, oops.

ResearchBlogging.orgNature (2010). A decade for psychiatric disorders Nature, 463 (7277), 9-9 DOI: 10.1038/463009a

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