The Shotgun Approach to Psych Drug Discovery

A foundation is offering to fund research into novel psychiatric medications, we read in the latest Nature Neuroscience:

The Broad Institute in Cambridge, Massachusetts has launched an initiative called ‘PsychHTS’ inviting scientists with ideas and data suggesting novel mechanisms contributing to psychiatric disease to apply for access to the Broad’s infrastructure and expertise for high throughput screening (HTS) of chemical compound libraries.

HTS is a clever technique for discovering new drugs, based on the crude but effective principle of trying hundreds of thousands of different chemicals until you find one which works, by using machines to automatically run the experiments (“assays”) extremely quickly. Hence, “high throughput”. It’s pretty cool.

The Stanley Medical Research Institute wants to use HTS to find new psychiatric drugs. There have been no truly new drugs in psychiatry for a long time: there are dozens of different antidepressants, for example, but they all work (if and when they work) by increasing brain monoamine levels, just like the very first antidepressants, iproniazid and imipramine, discovered in the early 1950s. The same is true of antipsychotics, which all block dopamine D2 receptors, just like the very first, chlorpromazine.

So new drugs for the mind would be great. But how are you going to find them by doing experiments in test-tubes, even if you have 50,000 test-tubes? The mind doesn’t fit in a test-tube. Here’s where the proposal gets a bit iffy:

Readouts may be anything from classical enzymatic reactions ... up to subcellular changes captured by automated high-content imaging. ... ‘Hits’—compounds that affect the assay results in a way that indicates potential usefulness in a psychiatric research context—are automatically retested at several concentrations...

So, the idea is that potential new drugs will be found by measuring how they affect certain cellular processes or chemical pathways. But which ones? Until we know what cellular or protein or enzymatic changes underlie mental illness, we won’t know what to look for. And the whole problem is that we don’t know much about that – if we did we’d have lots of new drugs already.

The article suggests only one route to finding truly novel mechanisms – genetics. In the past few years, there have been many genetic studies trying to find genes which cause mental illnesses. Some of them have identified risk genes which seem to imply new biological pathways. For example, the current orthodoxy is that schizophrenia is caused by abnormalities in the brain’s dopamine system. But the gene most strongly implicated in schizophrenia is called “neuregulin-1”, and it has nothing to do with dopamine. That’s interesting but unfortunately -

Recent genetic studies have indeed suggested new targets, but the identification of specific genetic risk factors remains elusive. The genetic results are themselves variable, often have small effect sizes and need independent replication.

In other words, the genetics evidence is so patchy, that using it as a basis for finding new drugs is like building a house on very shaky foundations. It might stand. But if the genetic links turn out to be spurious, all the subsequent research will have been in vain.

Personally, while I welcome any truly groundbreaking work in psychiatry, I would rather people spend time and money doing better research on the drugs we already have.

Nature Neuroscience Editorial (2009). Mining chemistry for psychiatry Nature Neuroscience, 12 (7), 809-809 DOI: 10.1038/nn0709-809