Effective CNS Drugs Are Where You Find Them

by: Derek Lowe

Here’s an interesting post over at Slate Star Codex (a site that generates a lot of them), on psychiatric drugs. The question is, what are the most interesting and potentially useful developments in this area over the last ten or twenty years? And the answer might well be things based on drugs of abuse:

The two most exciting developments in psychopharmacology in the 21st century so far have been ketamine for depression and MDMA for PTSD... I say these are the two most exciting developments mostly because no other developments have been exciting. In terms of normal psychiatric drugs, the best that the 21st century has given us has probably been pimavanserin and aripiprazole, modest updates to the standard atypical antipsychotic model. These drugs are probably a bit better than existing ones for the people who need them (especially pimavenserin for psychosis in Parkinson’s) but they don’t revolutionize the treatment of any condition and nobody ever claimed that they did. And most drugs aren’t even at this level – they’re new members of well-worn classes with slightly different side effect profiles. The landscape was so quiet that ketamine came in like a bolt from the blue, and MDMA is set to do the same in a couple of years when the trial results come out.

That may or may not be right about MDMA (phase III results have scuppered hopes like these in the past). But the point is a valid one. The ketamine story is an interesting and complicated one, with many twists and turns left, but its effects on major depression seem to be beyond dispute, even if we’re still trying to figure out how things work. There’s also a lot of interesting work being done with hallucinogens like psilocybin, and that one (like the two above) definitely did not come in through the usual preclinical development doors, either.

I think that the rationale advanced for why this should be so has a good chance of being right as well:

Here’s one hypothesis: at the highest level, the brain doesn’t have that many variables to affect, or all the variables are connected. If you smack the brain really really hard in some direction or other, you will probably treat some psychiatric disease. Drugs of abuse are ones that smack the brain really hard in some direction or other. They do something. So find the psychiatric illness that’s treated by smacking the brain in that direction, and you’re good.

Actual carefully-researched psychiatric drugs are exquisitely selected for having few side effects. The goal is something like an SSRI – mild stomach discomfort, some problems having sex, but overall you can be on them forever and barely notice their existence. In the grand scheme of things their side effects are tiny – in most placebo-controlled studies, people have a really hard time telling whether they’re in the experimental or the placebo group.

Nobody has a hard time telling whether they’re in the experimental or placebo group of a trial of high-dose MDMA. I think this might be the difference. If you go for large effects – even if you don’t really care what direction the effect is in – you’ll get them. And if you go for small, barely perceptible effects, then you’ll get those too. The dream of the magic bullet – the drug that treats exactly what it’s supposed to treat but otherwise has no effect at all on you – is just a dream. The closest you can come is something with miniscule side effects but a barely-less-miniscule treatment effect.

I think the brain has a lot of variables, myself, but I do agree that in one way or another, they’re all connected. That makes changing brain function a tricky business, and I’ve said for years (this is not particularly controversial) that we basically don’t know what we’re doing. A lot of progress has been made on subsystems of neural processing (check out this extraordinary paper that came out recently!), but the “higher” up the scale you go, the less we understand. Consciousness, emotions, reasoning, decision-making, temperament, memory and experience, mood, insight – you have to think that these things all come down to neuronal activity, that there’s no ghost in the machine, but we really have only very hazy ideas about what those activities are and how they might possibly work. Our tools are very crude, both in spatial and temporal resolution, and we can’t even be sure that we’re measuring the right things in the right ways yet.

So it’s true that some of the most dramatically effective therapies for mental malfunction are the equivalent of beating on the side of the instrument housing until something starts working better. And that’s why we can’t be sure which of these dramatic interventions (ketamine, electroconvulsive therapy, what have you) are the right ones to use in a given situation, or how well they’ll work. Our attempts to get more rational have been a mixed bag – a lot of small changes, as charged above, and even the successes have turned out to be a lot more complicated than we thought. How exactly, for example, do serotonin reuptake inhibitors help some patients with depression? We don’t actually know. Nor do we know why they don’t help some patients much at all, et cetera.

Human mental problems do bin into categories – not as neatly as in the DSM, surely, but they certainly do. And this suggests that either we all have some built-in systems that can go off track in similar ways, or that various derangements can send brain function off into similar low-energy states, or both. Paranoia, for example, is a rather common malfunction. The number of people who believe that enemies are reading their thoughts and plotting against them are beyond counting. But when did you ever hear of someone who was persistently convinced, against all logic, that people were sneaking around their back trying to help them? You can find all sorts of folks who think that the CIA or the Mossad or the UN have planted radio transmitters in their molars. But how many of them are happy about it, because the spy agencies have finally arrived to fix their problems? You see what I mean – we have brain circuits, very conserved ones, that are monitoring for threats and changes in our environment, and when those go haywire, you get Francis E. Dec and his many, many kinfolk. But the opposite is almost unheard of.

Taking observations like this, though, down to the cellular or biochemical level is another thing entirely. So I’m actually glad to see unusual therapies (like the ones described above) getting a hearing and getting a chance to prove themselves in the clinic. It’s going to be some time before we’re able to approach these problems in a more targeted, rational manner – if, in fact, there are indeed such approaches, which is still an open question. Until then, we need all the help we can get.

Disclosure: None.