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The Central Nervous System

How Antidepressants Work, At Last?

Over the years I’ve very much enjoyed being startled by the scientific literature, and there haven’t been many times when I’ve been more surprised than I was this morning. I’ve been making references on this blog for years about how we don’t even know how antidepressants work, but if this new paper is correct, then perhaps now we do. I’m amazed.

It’s from a multinational team led out of the University of Helsinki, and they have made some very interesting finds about the tyrosine kinase receptor-2 protein (TrkB). That has long been known to be a player in neuronal plasticity – TrkB is a high-affinity receptor for brain-derived neurotrophic factor (BDNF), which as its name implies, is one of the neurotrophic signaling proteins that can regulate the growth and branching of axons and synaptic density. These have been studied intensively since the 1980s as possible players (or treatments) in a number of CNS conditions – I vividly recall being on a (doomed) program that was investigating a related protein, nerve growth factor (NGF), for Alzheimer’s. Most of these work by binding to receptor tyrosine kinases – for example, NGF binds to one called TrkA.

The brain being what it is, it’s been hard to make headway on therapeutic uses of these systems, although they’re clearly extremely important. In recent years, a BDNF-centered hypothesis for depression has been on the rise. There are a lot of things about that idea that make sense, not least that it appears that BDNF levels seem to be correlated with features of depression itself in both animal models and humans, and it’s been shown that several known antidepressant drugs increase BDNF signaling through some unknown mechanism. The belief has been that this is an indirect effect of these drugs, because (after all) it’s already known they have high-affinity targets in the monoamine signaling system, e.g. the serotonin reuptake inhibitors like fluoxetine (Prozac). The same argument is made for the NMDA compounds, dopamine ligands, and the others, and it’s not a stupid idea by any means. If there’s one thing we’re sure of about these brain receptors, it’s that they have crosstalk with each other six ways from Sunday. So BDNF could well be a big factor, but there’s room to argue about all of this, as there is in most any important question about the functioning of the brain.

So one of the things this paper reveals is that a function of the TrkB protein is to serve as a sensor for cholesterol levels. I know that we’ve all been exposed to decades of public health stories to the effect that Cholesterol = Death, and when it coats the inside of your arteries that’s pretty accurate. But it’s also essential for life, as an irreplaceable component of every cell membrane. If anything, it’s even more important in the brain, where it’s been shown as yet another regulator of neuronal plasticity and is a big component of the myelin sheaths and the brain’s white matter. Out in the rest of the body, cholesterol is handled by a complex lipoprotein system involving the liver, the small intestine, and other organs that’s become famous over the years. But all this stops at the blood-brain barrier, and the brain has its own complicated system to import and distribute cholesterol to the neurons.

This paper identified a cholesterol recognition motif in the sequence of TrkB (which isn’t present in the related receptors). Addition of cholesterol to BDNF/TrkB systems had significant effects on signaling, and seemed to also promote the movement of TrkB protein from intracellular compartments up to the cell surface (which would also be expected to change the signaling landscape, naturally).

Now to the BDNF hypothesis. I used the phrase “unknown mechanism” above, and that’s exactly what this work may have cleared up. The authors show that when the TrkB protein forms a dimer in the cell membrane, a binding site for small molecules is formed at the interface. A whole list of known antidepressants (fluoxetine, imipramine, venlafaxine, moclobemide, ketamine, esketamine, and R,R-hydroxynorketamine) bind to this site at about 1 micromolar levels (and can displace each other in binding assays(, while a set of control CNS compounds like chlorpromazine, diphenhydramine, and indeed S,S-hydroxynorketamine do not. It will not be lost on those who’ve done research in the field that the antidepressant compounds listed above have been thought to work through completely different mechanisms.

But all of these compounds have similar effects on the TrkB-BDNF binding interaction – for example, they promote membrane trafficking of the TrkB protein itself. A very interesting tie-in is to the known effect of antidepressants on the number of AMPA receptors in the cell membrane, which has been linked to the antidepressant effects of ketamine and its derivatives. This effect is shut down by known TrkB inhibitors, so it appears to be downstream of the binding of the ketamine class to TrkB. It also appears that the shape and size of this small-molecule binding site is altered by the cholesterol-sensing functions of the TrkB transmembrane domain, and a prediction is that the binding would be most favorable in the most cholesterol-rich parts of the cell membrane. In what may not be a coincidence, that would the synaptic region in a neuron.

The authors do a good job of putting the hypotheses to the test by making various point mutations of the TrkB protein, and they show that they can disrupt the cholesterol-sensing function, the proposed small-molecule binding, and the BDNF effects by hitting key residues according to prediction. These effects are seen in binding assays and in super-resolution microscopy of the cell membrane, as well as in assays of neuronal plasticity itself. Finally, in a key experiment, it’s shown that such mutant forms of TrkB do in fact abrogate antidepressant drug effects in mice that express the altered receptor proteins. The results are very similar to those that you see in BDNF-deficient animals. There’s a lot of work that’s been put into this manuscript.

The cholesterol part of the story comes up in these experiments, too. The authors observed that the behavioral effects were also lost under acute pravistatin treatment (altering cholesterol homeostasis, and presumably having an effect on the TrkB small-molecule binding site as it senses a decrease in total membrane cholesterol). From what I can see, there no association has been found between statin use and depression (and it’s not like people haven’t looked!), but this is an interesting thing to consider. Perhaps if there is an effect it’s a transient one, as the brain then gets its cholesterol levels back up to a more acceptable range? Unknown.

All in all, this is an excellent and thought-provoking paper that has a lot of evidence backing it up. If these results stand up to further experimentation – and believe me, there’s going to be a lot of experimentation – then this is a major advance in our understanding of depression. Which would be very, very good news. I started off my work in the drug industry doing CNS medicinal chemistry, and was terrified about how little we really understood about such illnesses. It’s taken decades of work, but perhaps a key light switch has been turned on. Let’s hope so.

44 comments on “How Antidepressants Work, At Last?”

  1. Jonathan B says:

    Fascinating from your summary and a quick skim, I will have to go back and read the paper carefully given my rather rusty neurochemistry.

    But on the face of it it drives a cart and horses through decades of classic small molecule pharmacology on depression. Can it be that all those researchers – and drug discovery chemists trying to find better reuptake inhibitors etc – spent all their efforts studying a side effect rather than the causative mechanism?

    1. Grebs says:

      Looks like it doesn’t it. Better be sure of that target if you are going to play target based drug discovery.

  2. Bob says:

    Regarding statins – does it provide insight as to the difference between hydrophilic and lipophilic statins? I was originally put on a lipophilic statin, but had my PCP change that to hydrophilic based on possible associations with Parkinson’s, which I have a family history of.

    I see there is a 2018 study that found no significant difference in depression between the two types, but I’m wondering if this work sheds any light on the other possible associations, such as Parkinson’s.

  3. anon the II says:

    About 27 years ago, a little company that I worked for was going through another transmutation in order to survive. We became a high-throughput screening/combinatorial chemistry company. The CEO told a story about how, by the time anyone figured out that we didn’t know what we were doing, we might actually figure out what we were doing. I volunteered to be the technical lead on the combi-chem side. Anyhow, we managed to get bought by Lilly in 1994 and shortly afterwards, we got a visit from Bryan Malloy (, the inventor of Prozac, who came down to see what his company had purchased. I met with Bryan and we had a lovely chat. But, he let me know that he thought that what we were doing was no better than “pissing in the wind”.

    I guess this means that he was doing much the same.

  4. Eron Mot says:

    Does this mechanism shed any light on the ketamine anti-depressant results? Specifically, why ketamine appears to have anti-depressant results within hours, while the other anti-depressants take weeks?

    1. Cira Goettig says:

      Yes actually! They say:

      “It has been known for decades that the clinical response to typical ADs is only reached after several days or weeks of treatment, but the reason for this delay has remained a mystery. One explanation has been that the process of neuronal plasticity induced by ADs may take time to develop. However, the discovery of the rapid action of KET, which is also dependent on plasticity, has undermined this explanation. … Remarkably, micromolar concentrations of typical ADs are reached and required in the brain during chronic treatment, …. Importantly, typical ADs gradually accumulate in the brain, reaching a plateau after several weeks of treatment … suggesting that the clinical response is only achieved when the drug reaches a brain concentration high enough to interact with a low-affinity binding target, such as TRKB. Sufficient concentrations may not be reached in fast metabolizers or patients with limited compliance, which may contribute to the failure to respond. KET, on the other hand, readily penetrates to the brain to achieve sufficient synaptic concentrations quickly. Therefore, the gradual increase in brain concentration to a level needed for TRKB binding might be at least one explanation for why typical ADs take so long to act, while the rapid brain penetration of KET enables fast action. “

  5. ElephantMn says:

    I wonder if this is at all related to statins turning people into ragemonsters

  6. Dave says:

    Does this have anything to do with depressed people wanting to eat a lot?

    1. LdaQuirm says:

      Isn’t LOSS of appetite a symptom of depression? Careful what assumptions you sneak into your questions.

      1. Andrew says:

        Not necessarily – some depressives will overeat as eating is the only thing they get comfort from. The more common reason for overeating in persons with depression though is the side effects of antidepressant medication. Nearly all of them make the patient ravenously hungry!

        I did wonder, seeing the involvement of cholesterol in this if this is why eating fatty food feels so good!

        1. LdaQuirm says:

          I think you missed my point. “Some depressives will overeat…” vs his “depressed people want[…] to eat a lot” I was just pointing out a “why do you beat your wife?” situation. The fact that at least some depressives loose appetite, makes it either an over-generalization or just wrong. And what do you mean by “Not necessarily”? If A causes B in some people, then B is a symptom of A. It doesn’t need to be one to one.

          1. Andrew says:

            Sorry if I missed your point. All I meant that a depressed person doesn’t always have a decreased appetite. Particularly not if they are on medication for their condition

            Obesity in persons with severe mental health problems is a major concern these days. The increase in appetite caused by high doses of antidepressants and second generation antipsychotics combined with a lack of activity can lead to rapid massive weight gain

          2. DataWatcher says:

            Also, I think we need to make sure we’re not getting our causes and effects confused. Given the social stigma associated with obesity, I think it’s quite likely that obesity can be a predisposing factor for depression, not necessarily the other way around.

          3. albegadeep says:

            Andrew’s comment on depression sometimes causing obesity is a reasonable possibility. Certainly “comfort foods” are a thing (witness the common weight increase this past year, sometimes called “the COVID 19” (lbs)). If certain foods (like high-fat ones) help someone who’s depressed feel better, they may well eat more of them, increasing the probability of obesity for them.

            My overall point being, the cause and effect may in fact go both ways – sometimes weight gain can drive depression (ex. by social stigma), and sometimes depression can drive weight gain (ex. by comfort foods). And sometimes these can be a vicious cycle.

        2. Njia says:

          Also possibly the effects of sugar on dopamine levels and inflammation.

  7. Doug H MD says:

    so i had a senior attending while i was in training decades ago who made this very point:
    wondering why in studies of lipid lowering you often see more deaths due to accidents.
    And Swedish Prison studies demonstrated criminality with low cholesterol levels.
    His point was that any signal evolutionary for a person to nee to take risk in order to survive had to be a long term dietary signal. It would make no sense to go after that huge tiger if you were momentarily low FBS for example. But what if you were going to starve to death?

    1. PV=nRT says:

      It’s almost certain (but almost impossible to prove) that evolution has not selected for subtle behaviors as you suggest. Spandrels abound, meaning that behaviors that are more fundamental to survival were probably selected for directly, and effects related to depression came along for the ride, similar to how spandrels are decorations that hang on arches that are required for structural reasons in buildings — it’s a mistake to think that the arches are there to hold up the decorations.

  8. AVS-600 says:

    Very cool if true, but there’s something to be cautious about here:

    This looks like good evidence for a biologically-relevant factor that drives rodent behavior models for depression. But those behavior models are notoriously (and unsurprisingly) unreliable. Despite that, most of the time your company is going to want you to demonstrate some sort of rodent “efficacy” before you take something into the clinic, so it would make sense that marketed antidepressants hit this target. There is the definite possibility that this target isn’t going to translate into humans at all though.

    1. Mandark says:

      Very good point, animal models of depression are very poor. I’d add to that the fact that forced swim test (used in the study) detects immediate effects of antidepressants like SSRI, so how can it be valid for studying the “real” antidepressive effect that develops over weeks?

      1. Tommy says:

        Wow, just had to look that up and while I knew that animal models of depression were at least “inaccurate”, that kind of takes it to another level (in a bad way).
        Kind of shocking, if you think how often the test has been used to examine genetic impact on depression or to evaluate potential drugs…

        I mean in general if you think about it, the whole idea that a depressive mice just does not put that much effort into swimming/survival than a healthy one is a pretty shaky concept.

        1. LF Velez says:

          When I had an office in USciences’ Pharm/Tox department, I was utterly amazed to learn that we were basing some our determinations of “success” in treating “depression” in rodents by seeing if they were willing to swim to a small wooden platform rather than float despairingly in the water. There seemed to be waaay to many assumptions being made about what was going on — in both humans and rodents!

  9. David says:

    So many failed studies for gepirone, and other agonists at various subtypes of serotonin receptor. This might explain why.

  10. Marcus Theory says:

    Is micromolar binding enough? I don’t have a good sense of the concentration regimes you’d expect for these various different molecules in the brain, at efficacious doses.

    1. David says:

      Marcus Theory: “Is micromolar binding enough?”

      Karson et al, Human brain fluoxetine concentrations. The Journal of Neuropsychiatry and Clinical Neurosciences. 2016 v5 (3): 322–329

  11. Barry says:

    Do any of these drugs achieve micromolar concentrations in brain tissue at the recommended doses?

    1. Erebus says:

      Both fluoxetine and imipramine accumulate in the brain, and brain-to-plasma concentration ratios eventually reach 20-to-1 or 10-to-1.
      So… maybe. It’s possible.

  12. Albert Buchard says:

    Well packaged story. The only real evidence that this has anything to do with depression is the mutation study where they show a decrease in antidepressant effect.
    But that could be to a number of potential mechanisms and does not even have to be part of the same causal chain.
    This blog post is way too sensationalist to my taste.

  13. Iatrogenia says:

    The first mistake is assuming antidepressants “work”; that is, that they actually relieve or reverse depression. If they’re not effective at this fundamental task — and there is a great deal of evidence their effect on depression is marginal if it exists at all — reverse-engineering a reason why they “work” makes no sense. Most likely, these researchers unearthed a source for an adverse effect. But don’t let this interrupt the gullible hand-waving over miracle cures.

    1. Andrea says:

      The monoamine hypothesis was disproven decades ago. Hinz, M., Stein, A., & Uncini, T. (2012). The discrediting of the monoamine hypothesis.
      International Journal of General Medicine, 5, 135–142.

  14. Scott Alexander says:

    Would this imply that it’s just a coincidence that so many antidepressant drugs affect monoamines?

    1. The Edge says:

      There could be PK reasons you end up with monoamines. If being lipophilic and modestly basic gets you high brain concentrations, and most of your decisions are based on animal models, they would look more efficacious at lower plasma concentrations than more polar and less basic compounds.

    2. UserFriendlyyy says:

      lol my first thought after reading this was “I bet Scot Alexander will have an interesting post about this soon.”

  15. M. says:

    This is much better than many commenters here seem to think.

    Micromolar doses are indeed in reasonable range for longer term antidepressant use. And from the graphs, partial binding (especially in high cholesterol areas, such as synapse is expected to be) should be much higher affinity than that.

    While rodent models are limited, the results in light of molecular data is pretty strong. This isn’t a final result, or something that should be trumpeted from all rooftops, but it is definitely quite well supported and requires more work. It’s certainly a neat hypothesis.

    Also, “Iatrogenia,” antidepressants have questionable long term efficacy on mild to moderate depression. But it is completely countrafactual to claim they have no effect on major depressive disorder, where they quite certainly help a lot. And this is the part of the field where the monoamine effects were confounding for so long.

    1. Barry says:

      “partial binding”???
      Is this some innovation in PK?

  16. Nick M says:

    This could be a really interesting finding and explain many of the discrepancies seen in the clinic. Having spent years working on the development of ADs, it always troubled me that there seemed to be an act of faith assuming it was the acute reuptake effects that then translated into long term clinical efficacy. It would also explain the limited efficacy of direct serotonin agonists. As I have found over the years, selectivity is only as good as the number of targets you look for or know exist!

  17. Rock says:

    This study is very interesting. As another commenter mentioned, in the years leading up to the approval of the first statin, there was a heated debate around the prudence of lowering cholesterol. The debate was fomented by the British Medical Journal based on data from the Framingham Heart Study which demonstrated higher death rates in the lowest cholesterol group. This association was later drawn into question based on cause and effect. The subjects with the lowest cholesterol levels were found to have depression and therefore thought to have a poor diet leading to the low levels. Ironically, I often used this case study as an example of correlation vs causation. In light of this paper, perhaps those old BMJ articles should be revisited.

  18. DrOcto says:

    Derek the ‘doomed’ is always already implied whenever one refers to an Alzheimers program.

  19. lizzy says:

    Seems to apply to the Tricyclics, SSRI’s, SNRI’s, Ketamine and it’s derivatives but NOT if the antidepressant involves Dopamine or Allopregnalone systems. (Buproprion/ Brexalone)
    Perhaps we need to know more about GDNF and how to combine GABA-A and dopamine to decrease the addiction potential inherent in GABA system agonists.

    I’m glad Derek moved off the Covid target in this post and the semaglutide post. Depression, anxiety, and weight gain (Covid pounds) certainly have been major collateral damage areas in this pandemic. In addition, they are major Holy Grails in drug development.

    1. Anon says:

      Exactly…came here to bring up Buproprion (Wellbutrin).

  20. gippgig says:

    Could amphotericin affect this?

  21. Some idiot says:

    Hmmm…. Extremely interesting…

    Question: it is well known that for (eg) SSRIs, there is a significant proportion of patients that are treatment-resistant. Could it be that there may be another, commonly-occurring isoform of TrkB where the binding cavity has a geometry that does not allow binding of these compounds?

    Further, could there be some alteration to this system which may induce relapse? (another possibility is that there are better “pumps” to maintain a lower cellular concentration of (eg) SSRIs).

    My curiosity is at least partially based on personal experience. After obtaining a really good effect from an SSRI (relatively high dose) for around 15 years, I suffered a relapse (despite maintaining the dose; nothing changed there…!) and have spent the last 5 years or so shifting between other medications and medication regimes trying to find stability (short version: better than 5 years ago, but still not back to where I was).

    Another question (at least partially tongue-in-cheek): could my relapse have at least partially been triggered by the fact that my wife started a diet (a diet she still adheres to)?

  22. F. says:

    As you might know, typical antidepressants (SSRI’s and the like). are contra-indicated for bipolar depression as they can instigate a “manic switch”. Ketamine seems to be ok, however for bipolar depression. Does this study shine a light on new treatments for bipolar depression-a largely unmet medical need?

    1. Med Chem says:

      Seem to recall a TrK kinase an oncology target a decade or more ago. Bis-anilinopyrimidines and related series the leads at our sister site. Not the best chemical series, not the worst.

      Project didn’t play out – perm any from wrong target, wrong assay, wrong chemical matter, wrong selectivity, wrong model, wrong hypothesis, wrong PK, wrong therapeutic margin, wrong predicted dose, wrong timing, wrong commercial…

      …Except now seems it did play out elsewhere. Orphan drug status so far. Regulatory approvals in 2018 and 2019. Well done Array and Genentech for sticking with it and getting there in the end:

      Have to say can’t think about anti-depressant mechanisms independently of thinking about depression. Dabbled with on and off down the years. Who hasn’t? Much more off than on, thankfully, although did for a while take the lowest atomic weight approved mood stabiliser in the known universe.

      No contest when measured on an inverse log scale in pure unadulterated Daltons. The only conceivable lower molecular weight option might one day power your car, but will for certain never power your brain.

      Seems depression exogenous, endogenous or somewhere in between. That phone call resolved upon but funked, that earthquake from within. Even as recently as last year, that worrying over short term memory and inability to focus. Along with apathy, several depressingly depressive boxes ticked.

      Compounded by a perceived overbearing weight of over-reaction and over-disproportionality in the world outside. That late 60something Fenland Poly Prof interviewed in the Times, in effect saying, “Thanks kids for all the trouble you’re going through. Good of your generation to do the right thing to save the likes of me…”

      Oh FFS Prof Sir Emeritus, get off the kids’ backs, will you? Hey you, ged offa their clouds. In all probability, you and I have had at least three quarters of our go in life, they’re still on their first quarter. Let ‘em ‘ave their go, Prof, like you once did. Second thoughts, perhaps you didn’t – you are a numbers man after all.

      Mandatory masking in cavernous supermarkets the final straw. Had worked that one out already. A vast cavern ain’t a subway train. Well ventilated cavern involves minimal interpersonal transit time, moderate interpersonal distance.

      Backed up the other week by that football study from Denmark – 90 minutes played outdoors by 22 players measured up as all of 87 seconds within 1.5 metres of any other footballer on the pitch. Yet kids haven’t played football since before Christmas. Whereas the Elite Game has. All in bio-secure bubbles, you see. Bonkers bollox. Public Health dressed up as natural vectors of disease, glorified superstition and sacrificial offerings.

      And anyway, how come, shopping two or three times a week, week in week out, I’ve never seen anyone in a supermarket over the last year who looked the slightest bit unwell? All the ill staying at home, doing the right thing, eh Sir Prof?

      Only one thing for it – snap out of it. Switch brain back on. Work up informed opinion of “The Science” and the “scientific evidence, that’s “driving government policy.”

      When older, bit of philosophising can also maybe help. Experience gives meaning to existence? Existentialism? Jean-Paul Sartre? La Nausea? Thanks, but no thanks.

      Bertrand Russell and A J Ayer? Logical positivism? Always did like the sound of. Preferable to the double opposite. And yes, experience does give meaning to exasperation.

      Now moving, for illustrative purposes, onto family history, which can of course be highly personal. Those about to be mentioned have rested in peace many years and would by now, I think, perhaps consent to wordly resurrection, if context explained. Here goes anyway. In due course, my own descendents could say all sorts of things I won’t be around to hear. Their living prerogative.

      The elderly relative last said goodbye to nearly half a century ago. Everything touched turned to misery, although relatively speaking, only grandchild relatively immune from effects until double digit age.

      Depression, dementia, or just an intelligent mind, inferred by the family interloper to have been cossetted and mollycoddled by mother, father and much older brother?

      A younger woman who went straight from school to brother’s firm, and who grew up into an older woman who rarely came out into the sun? One of life’s illogical negativists?

      Those pictures on facing pages of the family album, taken at the same young adult age sixty years apart – that long face, those brown eyes heavenwards. So that’s who we next three generations look(ed) like…

      On the other side of the family, a robust logical positivist, most of the time a source of light and radiant heat. “I am the coalman, you are a sack of coal – I am carrying you on my back up, up and up the stairs, and Whoosh! I am emptying you into the bunker inside your noddy!”

      Although some time past double digit age, rallying and raging was from time to time heard come out swinging at injustices from up to eighty years earlier…

      …At the hands of a boozer, who’d gotten the taste for drink supping ale from the jug carried back home from the pub for the ritual grandpaternal end of working week family entertainment. Ah, the good old days.

      …And the rallying at the war to end all wars, the land fit for heroes to live in and the boy who lived on the other side of the marsh who never could keep his head down… and who didn’t stand a chance in France.

      Along with the three brothers from the well-to-do family at the bottom of the bank… who it turned out didn’t stand a chance either. Sergeant, corporal and lieutenant in descending age order, with a cousin, a private, also for good measure consigned to the War Graves Commission. Oh what a lovely war.

      Not much better on the other side of the family. The great uncle bearing a stretcher, who died a brave lad, felt no pain and fell with face to the foe. Or according to a second written eyewitness account – made comfortable and left in an old quarry. Either way, remains never recovered.

      The still rallying and raging at the boozer who ran away with all the money and spent it on the drink. Reputedly last seen turning up at the funeral in nineteen twenty four, hurling soil and abuse at the horse drawn coffin. Never saw the grandchildren or the great grandchildren.

      Ended up in Beddleston, still called the Loony Bin in open parlance of the time. Said to have been given daily doses of medicinal Guinness and stout to sup by the men in white coats right to the very end. Survived into the nineteen sixties. Or so the story went from the baby brother taken away in nineteen twenty three, along with all the money.

      “Man hands on misery to man, it deepens like a coastal shelf…” Doesn’t have to be that way. Stop the spread. Control the brain virus. Mania, hysteria, neurosis, depression, psychosis. You name it, it transmits.

      Easier said than done. If all else failed, by the nineteen sixties and seventies various pharmaceutical interventions on offer, of which Derek Lowe lists some. Lob in librium and valium too, and the non-pharmaceutical – behavioural, cognitive, psychotherapeutic, ECT, then still in fashion.

      From double digit age onward, saw whole caboodle taken up with close at hand. Happy families, eh? Ever since, tentative conclusion from latter-day med chem who never worked in CNS – drugs useful in acute setting, chronic use debatable? No intention to generalise – inferred from extremely limited dataset.

      Seriously though, maybe the TrKB-BNDF interaction really is central to how anti-depressant drugs work? Armed with this knowledge, perhaps chemists, neuroscientists and pharmacologists will join forces again, go back to drawing boards, novel test cascades and innovative clinical paradigms, and some years in the future come up with the potent, exquisitely selective, orally bioavailable TrKB-dimerisation up, down and shake-it-all-about regulatory modulator, CADENT…


      CAD only ever isolable as waxy amorphous pink crystals, best formulated as a micromolar solution in tonic water, seven up or diet coke. Far superior to Huxley’s nineteen thirties hooch that de-repressed an entire Brave New World.

      CAD might even end up approved for distribution in public water supplies. If we all agree it works, then it works. Bit like money, all fine unless we all want all our bucks out of all the banks at once. Don’t stop believin’. All humankind’s psychological difficulties solved in a single chemical entity. Somehow I doubt it.

      And lest med chem blog appalled at med chemist scepticism, should say about quarter century ago med chemist provisionally concluded, apart from likes of anaesthesia, contraception, dementia, upper range hypertension, non-addictive serious inflammatory relief, and seeing off invading fungi, protozoa, superbugs and tumours… when only 3-0 victory will do… best pharma, biotech and academia can maybe realistically hope for much of the time is 2-1 overall.

      Two thirds good, one third do no harm. Goes for medicine too. Much of rest of life as well, come to think of it. Although would still prefer driverless car, 737Max and all that’s ASD designed with 3-0 uppermost in mind, please, if I may trouble to ask, ‘cos even now I do still get anxious when planes make funny noises, worrying about dodgy drivers out and about on the road, and as for the instruction book for the burglar alarm, don’t get me started…

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