A recent correspondence on the topic of “Why aren’t there more drugs for the big CNS disorders” got me thinking about the topic. My take, having worked in the field, is that there is still so much unmet need in that area because we just don’t understand what's going on. It’s hard to come up with disease-altering therapies when you don’t really understand a single disease in the whole field.
Does amyloid cause Alzheimer’s, or does Alzheimer’s give you amyloid, or is amyloid just a sideshow? What sets off the chain of events that ends up killing off cells in the substantia nigra in Parkinson’s? What are the detailed molecular mechanisms of depression, or schizophrenia? Why don’t neurons remyelinate in multiple sclerosis? We don’t know. We know a lot more than we used to; we know more every year. But we don't know enough to cure anyone yet. Even in the areas where we know more than average, we still don’t know enough to step in with therapies that can do what people really want them to do.
By that, I mean do for these diseases what insulin does to Type I diabetes, or what antibiotics do to infections. To any working CNS researcher, such results in their field would be hard to distinguish from magic. We can’t even touch the surrogate endpoints, and do what statins do for LDL levels, or the various antihypertensives do for blood pressure. We understand those areas a lot better than we understand the brain. Even so, we still get surprised, as witness the controversy over Vytorin, and the various ongoing attempts to find something that will raise HDL – you push a bit beyond the mechanisms that you’ve worked out, and all sorts of things start to happen.
The best way I can illustrate how difficult it is to find a disease-stopping therapy for something like Alzheimer’s is to point out the incentives for one. Any drug company that came out with such a therapy would immediately have one of the most profitable drugs on the market, and they would go on to reap more and more money every year. Think of the sensation that a treatment that stopped – just plain stopped – schizophrenia. As I said, indistinguishable from magic. But the success that such a thing would have would be immense. The incentives are there; it’s just that the barriers are very, very high.
Of course, it may not be possible to do some of these things. I’d be very careful to rule anything out, at our current stage of ignorance, but schizophrenia may well be one of these things where a dozen (or a hundred) different pathways lead to the same roughly similar disease state. (Cancer, as I’ve said here before, is the best example of something like this). And even if it’s not quite that bad, it may be that the tangle of the disease just doesn’t lend itself to a single agent – that, I’d say, is quite likely. I strongly doubt if just stepping in and adjusting the D-whatever dopamine receptor a bit will turn out to do the trick. This doesn’t mean that it’ll be impossible to treat, it just means that it’ll be very complex.
And so it is, and so are most of the other big CNS conditions. I find it hard to explain to people outside the field just how complex these things are, and why progress has been so painfully slow for the patients who need these things now. It’s not that there’s no explanation. It’s that actually finding a drug that works for anything is ridiculously hard and expensive, a very difficult task by anyone’s standards. And CNS drugs are fiendishly difficult even by the standards of drug discovery.