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Effective CNS Drugs Are Where You Find Them

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.



40 comments on “Effective CNS Drugs Are Where You Find Them”

  1. Grif says:

    I suspect that “paranoid” delusions that people are helping you behind your back do exist. These are just less obvious and noteworthy, because beliefs of this kind tend to improve function or promote optimism, or are dismissed as harmless superstition, or present as dependency and impaired executive function.

    1. DCRogers says:

      It’s called “Pronoia” – the world is in a conspiracy to help you!

  2. johnnyboy says:

    “I suspect that paranoid delusions that people are helping you behind your back do exist”

    ie. the sizeable percentage of americans who believe in guardian angels ?

  3. Curious Wavefunction says:

    I think that these compounds are useful, but I also think they are blunt instruments that necessarily impact many neuronal systems simultaneously, so there’s going to be a huge amount of variation in individual response (including some pretty adverse responses). It would be interesting to see how much the positive effects of ketamine or MDMA hold up in sustained, large-scale trials.

    1. zero says:

      Powerful psychoactives are powerful. The psychological shock they deliver causes change. The direction of that change depends on the individual, but it can be guided. In other words, these ‘big guns’ should not be used as a standalone drug treatment. Clinical trials will need to carefully consider mental states when tabulating results.

      For best results, combine with counseling / therapy that prepares the patient for a dramatic event (and helps them recover from an adverse reaction). A parallel might be in OCD or phobia treatment, where several weeks of counseling prepare the patient for exposure therapy; the strong mental impact of facing one’s fears can drive a person to overcome them if they are ready to do so.

      Hallucinogens are known to have a ‘mood’ component that can be positive or negative. The person’s mental/emotional state and environment are significant factors in whether the experience is positive or negative. The actual chemical compounds likely have a tendency one way or the other, but more research is needed. Psilocybin has a reputation for positive outcomes, while compounds like LSA have a reputation for negative outcomes.

  4. brains says:

    Things with dramatic CNS effects that someone, somewhere might consider fun tend to end up in Schedule I rather rapidly. Who wants the added hurdle of overcoming that regulation (and the prejudice that your compound is labeled as a drug of abuse) when trying to develop a marketable drug? It’s taken MDMA decades to get to the point of having proper trials. Even if it shows great results in the new studies, I’m not holding my breath for its approval and availability as a prescription drug.

    Ketamine, as weird as it is, probably has an easier path due to already having FDA approval for other indications, and being in Schedule III.

    1. tangent says:

      It really seems hard to imagine developing ketamine for this indication if ketamine were a new drug! Wouldn’t you be laughed out of the room for the effect profile? Or realistically would it even cross your mind that this could be a legitimate candidate, that it could pass toxicology?

      1. Old Timer says:

        Could you elaborate? My limited knowledge of ketamine is that it has a great profile for a anesthetic. You get anesthesia with hardly any respiratory depression. That in itself makes for a pretty compelling case to move the compound forward. The fact that it had some (unusual?) CNS effects pre- and post-treatment seems well worth the added safety relative to other anesthetics.

        1. NJBiologist says:

          Ketamine monotherapy doesn’t give you respiratory depression, but it also doesn’t give you muscle relaxation. In veterinary practice, the result is co-administration with a muscle relaxant–which is usually a respiratory depressant. In human practice, the result is that the anesthesiologist shrugs, decides that they spent all that time as a resident managing respiration, and switches on the gas. Or propofol. Or something besides ketamine.

          Much of the current human use of ketamine is for a limited set of practices (changing dressings on burn patients) with a list of contraindications (young, or old) and plans in place to manage those CNS side effects (apparently, benzos work well to manage the hallucinations/paranoia).

          1. Old Timer says:

            Interesting. I know an anesthesiologist in the Netherlands who uses ketamine rather frequently and often ruminates aloud how he doesn’t understand the lack of wider adoption in the states. He loves the safety profile and has limited complaints about the CNS after effects. My guess is that US MDs are much more sensitive to the politics instead of the actual data.

        2. tangent says:

          Sorry, I meant to develop it for depression. If it weren’t already a drug — say if it had some flaw that made it ineffective for anesthesia (without affecting its profile in depression).

  5. tlp says:

    >> 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?

    A quote from Paulo Coelho:
    “And, when you want something, all the universe conspires in helping you to achieve it.”

    There are people who actually believe in that. No survival curves compared to paranoid ones though.

    1. Peter S. Shenkin says:

      Yes… I was gonna say, perhaps most members of fanatical religious sects who believe that “God wants us to do” whatever (which might be good or evil in conventional terms) “for our own good, and that of others.”

  6. bacillus says:

    Invega Sustena and Invega Trinza (slow release injectable once a month or once every three months respectively paliperidone) may not represent any great advance in chemistry, but it has been revolutionary for my schizophrenic son and his parents. Trinza in particular has literally given him a normal life. Gone are the days of me acting as his prison warden to ensure compliance with tablets. Sustena was good, but he tended to get moody for the last few days. It’s the same with Trinza, except it’s now only a few days every three months. I dare say many other schizophrenia sufferers will experience similar benefit.

    1. Istvan Ujvary says:

      BWT: Remember risperidone, mother substance to paliperidone, was discovered using an LSD model of psychopathology?

      Furthermore, on current MDMA-trials (controlled or uncontrolled): all are being done with the racemic stuff. I don’t know whether this was intentional or merely an oversight or had drug-political reasons behind. Yet, it is a missed opportunity to discover the true medical potential of MDMA.

      1. tangent says:

        Doesn’t seem like a terrible idea to me, to run using the same racemate that previous pilots and informal trials used, and got promising results from.

        Do you think using the R would give better results, that that S is interfering with “true potential”? It might reduce speedy side effects from the S, but if the whole side effect profile was already considered tolerable, why rock the boat, I’d think.

        For that matter who knows if the S isn’t helpful too. The “pressure of speech” effects of amphetamine, in moderation, could be of benefit in short-term talk therapy, perhaps.

        Don’t get me wrong, I’d like to see an R comparison arm, but I wouldn’t run that as the first and only either.

  7. Anon says:

    Basically it’s a question of risk vs return: If you want high return (i.e., clinical benefit) then you have to set the bar high and accept high risk (side effects). But conversely, if you first set the bar for low side effects, then you can expect little return/benefit.

  8. CR says:

    Don’t know why it’s so hard, the brain is so simple. Or so, Neil deGrasse Tyson believes.

  9. Diver Dude says:

    Having spent 30 years working in psychopharmacology research (on everything from epilepsy to schizophrenia and points in between), I’d make one further recommendation. Try to get a molecule that hits as many receptor systems as possible with approximately equal affinity. There’s no guarantee, or even reason to suppose, that similar CNS symptoms are caused by similar CNS pathologies. At least this way you give yourself a racing chance of affecting the problem in a population of patients. Chlorpromazine would be my suggested model. It was not called Largactil for nothing.

  10. Daniel Barkalow says:

    MDMA is interestingly different from most conventional CNS drugs in that it’s being used during a medical intervention (a psychotherapy session), not during everyday life, so it’s okay if it has major side effects. It’s not like sevoflurane (the general anesthetic) would be acceptable as an outpatient treatment, but the side effects (unconsciousness, paralysis) aren’t a bad thing during surgery.

    It’s also important that MDMA isn’t being used by itself, so they’re not trying to find a drug that cures some precise condition; it’s probably best to say that it’s being used to make it possible to use the standard treatment (talk therapy) in patients who don’t tolerate it under normal circumstances. It’s probably unrealistic to think that, if you give the brain a big random whack, you’ll make it settle back into some better state. But while it’s unsettled, you’re pretty likely to find that it reacts differently to the fine-tuning that you’ve been trying to do but failing due to its usual reaction.

    1. tangent says:

      Yeah, this is a good point, that MDMA mostly doesn’t pharmacologically cure the condition, it works with therapy. Psychedelics are generally applied similarly. Therapy gives a whole different handle on the brain than just whacking it with a drug.

      Similar kind of example is using beta blockers as part of exposure therapy for a phobia.

      What are good non-CNS examples of this combined modality? Use of pro-osteoblastics as part of physical therapy for fracture. I bet there are other PT examples?

      I guess you could say lots of drugs — anesthetics — enable surgical interventions, but that doesn’t seem quite on point.

      1. milkshaken says:

        MDMA is typically used racemic (not just for the ease of manufacture – the drug users like the racemate better, as the combined effects are more enjoyable) but the two enantiomers have vastly different properties – R is psychedelic, S is amphetamine-like stimulant

  11. AC says:

    “someone who was persistently convinced, against all logic, that people were sneaking around their back trying to help them?”

    I’ve known quite a number of people that have suspected this to a small degree. Impostor syndrome seems to be very common in graduate students and a number have told me that they suspect that professors/teachers/peers have secretly helped them along or conspired to help them into positions that they don’t deserve to be in.

    1. zero says:

      That really sounds like they don’t believe they deserve what they’ve achieved. Since they clearly aren’t smart/awesome/whatever enough to have gotten that position/promotion/whatever on their own, clearly it must be the work of outside forces.

  12. Shane says:

    Could the focus of drug development be related to the economics of therapy, in that a drug with a strong effect that is used short term is potentially a lot less profitable than one with a mild effect that is used for the rest of your life? Add in the greater chance of serious side effects with the stronger agent contributing to lawsuits and making approval harder to get and you have a recipe for aiming low in terms of therapeutic impact. Assuming such a thing is possible, what company would wish for a single dose pill that cures depression for life ?

  13. Pennpenn says:

    “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 mean apart from almost every religion I’ve ever heard of? Ok so it’s not “people”, but that’s basically one of the major selling points, that a god or whatever is acting to protect, guide, and aid the “faithful”.

  14. Concerned says:

    MDMA, ketamine, psilocybin…all of these can cause some very unpleasant symptoms such as panic attacks and activation of latent psychosis. Some of these symptoms can last for years. I would want to see some very, very good large-scale data before I can trust regular prescriptions for these potent compounds.

  15. Barry says:

    It’s likely that hydroxy-nor-ketamine is a more interesting lead for anti-depressants than ketamine per se. When we rely on metabolic modification of a pro-drug, we introduce a world of irreproducibility between patient and patient that can sink a clinical trial. And of course the “side effects” of ketamine as anti-depressant are pretty impressive, even calibrated against existing, approved anti-depressants.

  16. Neil says:

    As a mid level marketer for a global company supplying SSRIs, I have several clear recollections from this period (early 2000’s). The first was a noted psychiatrist stating that in placebo controlled trials, active comparators only showed separation in about 50% of studies. The second was the short duration of studies e.g. 8 weeks when actual usage went on for many, many years. Concerns about suicidal ideation were dismissed by a Med Dir as it didn’t translate into an increased risk of suicide (I always felt that if you had sufficient patients in the analysis you’d find a positive association). Finally, the difficulty in coming of therapy appeared understated. I’m sure the class has helped many patients but I never felt comfortable with the role and was grateful for a switch in therapeutic area.

    1. Barry says:

      Drugs (CNS and other) that will be administered for decades should be safety checked for decades. That can’t (and shouldn’t) be done before FDA approval. But it must be done in “Phase IV”. We’re only now learning the risks of chronic administration of e.g. bisphosphonates when they’re given many times longer than the tox. studies on which they were approved, even though we knew that they never clear.

  17. DN says:

    “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?”

    I have read that people with mania often have an irrational belief that the whole world loves them. They think that the trees are sending them beams of pure love. There is no suspicion of sneaking around behind their backs, but they nonetheless think they are the chosen ones.

  18. tangent says:

    No silver bullets for the brain? This makes sense to me on the basis of “information content”: we have a limited number of knobs we know how to twiddle on the CNS, and most disorders don’t line up well onto “one knob is too high/low”.

    Because the majority of our knobs relate to neurotransmitters, don’t they? So your universe of options includes agonist/antagonist at a basket of receptor subtypes, possibly some allosteric opportunities, maybe transporters, probably go up/down on synthesis and degradation. We might have half a dozen different knobs on one neurotransmitter and a dozen on another. And I know there are other targets — intracellular ones, proteins controlling cell behavior — but how many have we drugged?

    So how many basically different CNS drug intervention paths do we have? What, order of a couple hundred or so? There are so many ways for the brain to get messed up, and most of them don’t actually map onto “this knob needs to go up a notch”.

    Probably many of them want “this knob needs to be adjusted in response to other conditions”, which is tough for a drug. Some of them want “increase in this location, decrease in that location.”

  19. aairfccha says:

    Great. Now imagine the prohibitionists hadn’t managed to hold back research in that direction for about 40 years…

  20. Morten G says:

    I don’t really see it as that controversial. Plenty of people are successfully microdosed on amphetamine and methylphenidate (amphetamine analogue).
    LSD is apparently also big for depression. Hundreds of news articles on that but here’s one:
    And another:

    I don’t know if antidepressants have done enough against suicide. The data over time looks mixed to me:
    Dramatic effect in Denmark. Some in Germany. None in US/UK. Weirdness in France and Norway.
    Wait, Greenland is probably included in the Danish statistics… So that’s invalid…

  21. JonB says:

    2 thoughts:
    –Actually quite a few interesting novel compounds in psychiatry that have excellent efficacy:tamoxifen for bipolar, pioglitazine for depression, buprenorphine for depression, and our old friend ketamine. Oops….they are all generic and there is no money to promote large scale use even if the institutions conducting the DBPCT research trials are well recognized: NIH, Harvard, Cleveland clinic, etc. Marketing and post-marketing studies are very important. Bipolar disorder was a fringe topic until Abbot spent a lot of money promoting Depakoate.
    –Paranoia is a manifestation of inadequate synaptic pruning in areas dedicated to social cognition.. Pyriform cortex (EQ) and archicortex (IQ) have different embryological antecedents so it is possible to see paranoid psychosis without intellectual decline in full-scale schizophrenia. Good luck trying to persuade the FDA to allow a trial of an agent which degrades memory density….

    1. tangent says:

      Cool stuff, I hadn’t been aware, thanks for bringing those up! Review articles I found to start:

      Protein kinase C for bipolar

      PPAR-gamma for depression

      Were these found like ketamine, by anecdotally noticing mood effects in people taking them for other reasons? Or was it driven by “rational design” disease biology, then taking up a convenient approved drug to apply?

  22. Depressed says:

    The rapid acting anti-depressants ketamine (and derivatives), rapastinel (GLYX-13), scopolamine, mGlu 2/3 antagonists, appear to all require the activation of postsynapic mTORC1 which is directly linked to increased synaptogenesis which is critical for their antidepressive efficacy (at least in animals). Direct mTORC1 activation may be a novel approach to a new class of antidepressants and possibly other CNS disorders where regulated synaptogenesis is beneficial.

  23. Sympa says:

    I remember a friend who told that he had great preventing or curing his migraine by taking a low dose of some mushroom.
    I remember this being a really low dose, way under the recreational level.

    And do not forget that ‘classical’ meds also are dose-dependent (duh).

    1. tangent says:

      And sure, given that ergot alkaloids are standard for it, right?

      Also for cluster headaches:

  24. Dan says:

    Derek: the brain has a lot *going on* but when you really look at the systems involved, I’d argue there aren’t that many. You’ve got Serotonin, Dopamine, GABA, Adrenergic, Histamine (I wouldn’t *really* count this one but a lot of atypical antipsychotics hit histamine receptors), and Acetylcholine. That’s about it when it comes to broad receptor categories, and most drugs that hit one in a category have a greater or lesser effect on all of them (excepting serotonin agonists that don’t hit the brain but affect the gastrointestinal receptors).

    I think a good case can be made that our most potent psychiatric drugs like antipsychotics with indications for major depressive disorder as well do just what you said, they whack nearly every one of those systems, to a greater or lesser extent. Look at something like Quetiapine, its receptor activity is basically “yes”. AstraZenica published activity reports showing clinically significant activity at basically every receptor that we know of.

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