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Understanding Antidepressants – Or Not

I was talking with a colleague the other day who’s done a lot of work on central nervous system disease over the years, and it reminded me of something that I said years ago on this blog (and was the first time I was quoted in the Wall Street Journal). Was that an opinion about some company’s stock or the biopharma climate? Nope: it was the statement that “we don’t know jack about how central nervous system drugs work”.

I’m still willing to stand by that one, although it’s certainly true that there are some drugs (and some categories of drugs) that we understand a bit better than others. But my point was directed to what people outside the field might imagine that we know about (for example) drugs for depression. Think about that one – it’s a very serious problem for those suffering from it, there are a lot of such people, and there are quite a few drugs for the condition, some of them famous and recognizable enough to have appeared in book titles. A lay observer could easily be forgiven for thinking that we understand how antidepressants work. But we don’t.

It’s a famous enough field that even the stated mechanism-of-action of many of the drugs in it is known to far more people than most drug mechanisms. Ask ten thousand random people how ibuprofen works and I don’t think you’ll get very far. But ask them how Prozac works, and I’ll bet someone pops up and says that it makes your whatchacallit, serotonin, go up. Serotonin is that stuff that makes you feel better, you know.

Well, that is actually what Prozac and the other SSRI drugs will do, up to a point – they will definitely affect the serotonergic signaling in the your brain. Past that, though, I would not want to put any money down, except against the proposition that serotonin levels = happiness. The unofficial motto of all CNS research is “It’s actually a lot more complicated than that. . .”, and so it is in this case, too. The long search for connections between serotonergic-related gene variants and depression has been frustrating in the extreme, for example, and if the story were a simple one you’d have hoped to find something there.

Here’s a review of the field from a drug discovery perspective, and the references therein make several points clear. The response rate to the SSRI drugs (and all antidepressants) is variable and unpredictable. Large numbers of patients show partial responses, at best, and many of them discontinue the course of treatment. The efficacy of the newer agents is not provably better than the older ones, although (since they have fewer side effects) people are willing to stick with them longer. In some cases that’s a good thing, because the onset of what beneficial effects there are can take quite a while to show up. And sometimes there are beneficial effects for a while, which then slowly disappear.

If we knew more about what was happening in the brain during depression, we might be able to do better. But that takes us back to the first paragraph: what happens, on a neuronal level, when a person has an onset of major depression? Despite a great deal of work on this question, we still have to throw our hands up in the air. The number of factors at work, the subtlety of their interplay, and the crudity of our tools with which to study them all conspire to keep us ignorant of the real story.

Let me say here that I’m not a nihilist: I believe that there is a real story, and that we will eventually know it. It could turn out to be something like “If you have more than X% of Type 473 neurons in subregion 79Q of the forebrain, you’re at risk for slipping into Alternate Neuronal Network Firing Patterns #2907 through 3043 if the balance of long-axon activity decreases, potentiating a feedback loop of protein synthesis that produces mixed-GPCR phenotypes #973 through 1028, spreading distally through axonal networks 384 through. . .

But we have no way to tell anything about this level of detail in a living human brain, in neither the spatial nor temporal resolutions needed to start tracking patterns like this down. We’ve made vast amounts of progress, but it’s still like trying to map out how each snowflake fits together with its neighbors in a huge drifted pile. Actually, that would be easier: snowflakes are all roughly the same size compared to the variations between neurons, and they’re all made out of water, as opposed to having tens of thousands of proteins scattered through them. And, of course, they’re not constantly all talking to each other, or not that I know of.

The most progress has been made on brain function in its more mechanical aspects (such as the visual cortex). That is very much hard enough, but when you start moving into higher brain functions like cognition and emotion, you have most certainly slipped the surly bonds of earth as far as mechanistic explanations go. I’m in awe of the brain, and yes, it does indeed give me the creeps that the phenomenon of “being in awe” depends on my brain as well. Consciousness is one of the hard problems out there.

But we don’t need to understand consciousness (fortunately) to have better antidepressants than we do now. In fact, I think that useful agents are more likely to come empirically. Our progress is not going to be pretty, and it’s not going to be swift and sure, but as we investigate more combinations of neuroactive agents and look out for more effects of existing compounds (of all kinds), I actually think that the chances are good that we can come up with something better than we have now. Admittedly, that’s partly because what we have now isn’t that great. It’s going to be quite a while before we can take pride in our detailed cellular and molecular understanding of depression – but in the meantime, I think that we can still help people suffering from it, and if we can’t take pride in that, no matter how we stumble up on the treatments, what can we take pride in?

70 comments on “Understanding Antidepressants – Or Not”

  1. Marcin says:

    So how is that whole Brain Atlas Institute doing?

  2. BipolarChemist says:

    Can we also address the fact that for over 50 years people know for sure that Li works wonders in mood regulation, yet we have absolutely no idea how and why? My (Li-sustained) mind is blown by it. Of all the medications for bipolar treatment out there it’s the only thing known to work in every case, and yet it’s a mystery. Clearly, it’s trickier to figure out the multitude of ways in which one tiny ion affects the incredibly complex CNS chemistry compared to large-ish organic molecules that bind to specific pockets of specific proteins, but nonetheless, the lack of understanding is astonishing. I feel that getting a better grip on the Li mode of action might shed some light on the fundamental processes that are guiding mood regulation.

    1. Derek Lowe says:

      An excellent example. There have been a number of proposals over the years, including some recent ones, but to the best of my knowledge it’s still a mystery!

      1. Marcin says:

        Has any researcher implicated aquaporins?

        1. Anon says:

          You just now? 😉

          1. Marcin says:

            VINCE?

    2. tlp says:

      One of my earliest posts was about Li effect on bipolar patient-derived iNeurons. You can check it (linked in the nickname) or the study itself https://www.nature.com/articles/nature15526
      I didn’t look for follow-ups though.

    3. skeptic says:

      Weak interactions are harder to study than strong interactions. I’d say the poster child for CANS ignorance is still general anesthetics.

      1. skeptic says:

        CNS not CANS.

  3. So the comment about few in 10,000 people knowing how ibuprofen worked tweaked my curiosity. I vaguely recalled that it was a COX inhibitor and this had something to do with prostoglandins, but felt obligated to check Wikipedia (all hail the repository of all human knowage) to refresh my memory. The article mentioned that ibuprofen is practically insoluble in water. So how does that work for a drug taken orally? (I’m just a humble country astrophysicist, not a chemist or biologist.)

    Curiously, I first encountered the word “prostoglandin” in an article in Reader’s Digest, back when its business model was still to excerpt the best articles out of other publications for its presumably intelligent, well-educated, but busy readers. I think the public has gotten stupider since then.

    1. Barry says:

      Water-solubility is definitely the exception among modern drugs. But remember that blood is thicker than water. Proteins in the blood (mostly albumin) can carry chemicals into solution that won’t dissolve in water alone. This also keeps them around longer. A water-soluble drug of Molecular Weight less 3,000 AMU would quickly be spilled out through the kidneys if it weren’t bound to albumin.

  4. Wavefunction says:

    Now imagine trying to model the action of CNS drugs. It would be a whole lot of hokum. We can barely model CNS penetration trends, even qualitatively.

    1. Chris says:

      The difficulty of modeling any complex physical or chemical system is a nightmare. I keep getting people asking me about modeling the solid / liquid combined reaction systems I work with with CFD. By the time I finish describing the realistic structure of a packed bed of wood chips, the CFD guys have gone white. And that is just a physical system. The challenges of understanding brain mechanics I don’t even want to consider.

      1. Wavefunction says:

        Ah, that would indeed give me the heebie jeebies. I always say that part of being a good modeler is to know when to tell your colleagues that they are better off testing things empirically. The one thing I would say is that this kind of challenge in modeling the mechanics or physics of a system is why data-based approaches like machine learning are attractive at least in principle. There you treat the system as a black box and make predictions purely based on the trends in the results. Of course these approaches carry their own baggage, but they will hopefully offer a viable alternative at least in the future.

        1. Anon says:

          When there are more degrees of freedom (independent variables) than the number of observations (dependent variables) you can possibly measure, you know that any kind of modeling will give you a pile of meaningless noise and spurious, misleading correlations. Even more so when the intrinsic quality of data is low.

          I wish people would consider that obvious fact of information theory before harping on about the potential of AI, digital and “Big Data”.

          1. Wavefunction says:

            Indeed, and that’s why we worry about domains of applicability. If a few variables contribute dominantly then there are limited cases where the model works well. It’s why congeneric series often benefit from methods like FEP.

          2. Doctor Memory says:

            …or, for that matter, economics.

  5. MBP says:

    The link for the words “not provably better” is broken

    1. Derek Lowe says:

      Something seems to be going wrong with PubMed right now – fixed soon, one hopes. Every hit I click on in a search comes up as “not available”, although it was fine earlier today.

  6. luysii says:

    Even if we knew how our drugs affect all the players at the synapse and beyond, another major problem is that we simply don’t know all the players. Who would have thought that a presynaptic protein is a remnant of a retrovirus, forms a capsule and schlepps mRNA (and other RNAs) across the synapse. Yet there is evidence that exactly this is the case. For details see https://luysii.wordpress.com/2018/01/14/why-drug-development-is-hard-31-retroviruses-at-the-synapse/. The protein is Arc (Arg3.1) and the work was reported last month in Cell

  7. Jenna says:

    You make many valid points; however, as a therapist myself, I can vouch that side effects are everything to my clients. Most of the older drugs note “suicidal ideation/thoughts” as a common side effect. That is a HUGE issue, especially in clients with a history of suicide attempts. Many of the newer drugs do not claim this to be a common side effect, which makes a big difference in the long run.

    1. HTSguy says:

      Not only do tricyclic antidepressants have “suicidal ideation/thoughts as a common side effect”, but they are much more likely than SSRIs to kill you if a large overdose is taken.

    2. Derek Lowe says:

      Definitely – that’s why I mentioned that people are much more willing to stick with the newer agents. And since they do some good in some people, it’s probably led to more people actually getting some benefit.

  8. Lane Simonian says:

    I am not a pollyanna, but the level of skepticism and “we are almost completely in the dark” zeitgeist in science is still troubling.

    Part of it begins with the sense that you can only know anything by personally conducting experiments and nothing is worth anything until you have conducted phase three clinical trials. Certainly there are severe limitations in mice models and phase one and phase two clinical trials can produce misleading results as well, but going to the other extreme and concluding that they are all worthless is a problem as well.

    The inductive method in science is not dead, but it certainly is depreciated in many quarters. Yes, scientists still usually do literature reviews, but that is rarely their main focus. The real work is done in the lab not in a den (or these days in front of a computer screen).

    Here is one exception: an over one hundred page literature review of oxidative stress in various disease followed by 1,478 references.

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2248324/

    Certainly much is missing. However, just because we are missing a detailed blueprint does not mean we should ignore guides.

  9. Uncle Al says:

    Depression is chronic temporal ullage to be filled with soap operas; alcohol and tobacco; “mother’s little helpers,” et seq. – echoes of purposeless people. Ban refrigerators (daily shopping), washing machines, dishwashers, vacuum cleaners, shampoo (to the hairdresser!) and contraception (plagues of children).

    SSRIs cause xerostomia and xeropthalmia. Depressed patients know it is “working,” support the bottled water industry, join vocal social support groups. SSRIs cause global annoyance and contingent recursive mass whining, filling time.

    1. Marcin says:

      Good for premature ejaculation too!

    2. What utterly cruel drivel. Talk to someone who has suffered depression – or know one while they are going through it – and you would never babble so idiotically. Or just read of famous leaders completely lacking “mental ullage” – Churchill or Sherman or Lincoln yet burdened by depression

      1. Uncle Al says:

        To criticize is to volunteer. Enlighten us with the true cogency of depression. Liberals are “We must do something!” happy warriors with others’ assets. Conservatives are “We must do something pertinent,” depressed with burdens of responsibility, contingency, and their own wallets.

        One cannot drug the Obamas’ portraits into objects of value. One can only drug the audience into denying their own lying eyes – hence your scree.

    3. me says:

      I look forward to seeing your comments Uncle Al! It’s a rare talent to write just on the edge of cogency and utter insanity.

    4. Pennpenn says:

      This is the stupidest thing I’ve read all day, and while it’s not gone midday here it looks like a promising contender nonetheless.

      I mean, each one of those would cause more problems than all of them together could possibly solve (and seriously, “go to the hairdresser”? Every other day. Riiiiiight).

    5. Paul says:

      You have no clue what you are talking about.

      1. Passerby says:

        You fine folks pay no mind to ole’Uncle Al now. He’s been hovering on the edge of sanity since the early days of the chemical blogosphere. Just think of him as your crazy Thanksgiving uncle.

        1. anon the II says:

          Is this the same guy who used to be on the Usenet back in the 90’s, answering organic chemistry questions for struggling premeds? He used to be mildly useful back then. I wondered what took him so long to find this blog. If it’s the same guy, he seems to have gone off the rails a bit. Maybe Health Services should check in on him.

          1. Doctor Memory says:

            The same, although his politics were quite entertaining back then too if you ran across him in the correct fora and mood.

    6. Anon says:

      War is also a good distraction/cure from introspection and depression. Not to mention disease and famine. Those give perspective and purpose!

      1. Uncle Al says:

        Correct! It is better to be whipped than ignored…and best of all to wield the whip (and an expense account).

    7. Doctor Memory says:

      I had wondered if you were the same “Uncle Al” that I recalled from Usenet and some alluvial web comment boards. It seems that it is so.

      1. Uncle Al says:

        Let us respect Dr. Lowe’s party. When you need research in the worst way possible – Uncle Al’s way. So it can’t be done, so what? Biology is a much tougher nut to crack.

  10. Officer John Gillespie Magee Jr. says:

    Please reference me. From beyond.

  11. hn says:

    I have a more optimistic outlook. Considering we don’t know jack about how the brain or psychoactive drugs work, we’ve come up with a broad and useful pharmacopeia for patients. We will likely do better as our knowledge of brain science grows.

  12. Barry says:

    As you note
    “we don’t know jack about how central nervous system drugs work”.

    Before even we had Lithium for bipolar disorder, we had ether and chloroform (and later cyclopropane (“trimethylene”), and halothane…) as anaesthetics. And still no one knows how they work (or what consciousness is)
    Time and again, when I grumble about the poor correlation of animal models to human cancer, someone laughs, because she/he is working with animal models of CNS diseases.

  13. Mark Thorson says:

    How do we test antidepressants? There’s the Hamilton Scale
    which is a questionnaire for humans. There’s the Forced
    Swimming Test which is a tortured rodent model that seems
    to correlate with antidepressant effectiveness. Other than those,
    nothing. There was a clinical study in JAMA — I think it was about
    three years ago — which tested St. John’s Wort against placebo
    and an active control arm, setraline (Zoloft brand). It found that
    SJW didn’t exceed placebo, but neither did setraline. I think
    that would be a surprise to the users and prescribers of Zoloft.

    Face it. As medicinal chemist Barbie says “Quantitative
    measurement of depression is hard”.

  14. Diver Dude says:

    I spent 25 years working to develop human models of disease in CNS drug development. It left me stressed and unhappy, if not formally depressed. Maybe that’s our model right there.

  15. Passerby says:

    There’s also cognitive behavioral therapy (CBT) which has been shown to work as well or even better. Given the side effects of these drugs, CBT should really be the first line of approach for treating depression. Unfortunately CBT takes time and we live in a society which likes quick fixes and pills, even if they seldom work.

  16. AQR says:

    Having worked on antidepressants for a sizeable fraction of my 30+ career, I find it humbling that, while we know that SSRIs work by elevating extracellular serotonin levels in the brain, we don’t know which of the dozen or so serotonin receptors mediate the effect or in what part of the brain they function.

    1. luysii says:

      Hear hear ! This can bear much further repetition

  17. steve says:

    The discussion all assumes that depression is due to defects in neuronal signaling but this is just conjecture. There are very good data that, at least in some (most?) patients depression is linked to inflammation. As just one example, a recent paper in JCI showed that patients with depression had 46% higher levels of C-reactive protein (CRP). People with inflammatory diseases get depression during flareups that resolve during the resolution phase. There is also the recent (last week) paper in Science showing similar gene expression patterns between autism, schizophrenia, bipolar disorder and depression. The intersection of inflammation and these gene expression profiles may be a very fruitful area of research.

      1. Ian Malone says:

        Ah, if I see hindawi or omics in a referenceI need a good reason to bother looking at it…

        (I realise that your comments normally get a lot of scepticism on this blog, but that’s not where I’m coming from here. They have a fairly poor reputation and a pay-to-publish model with, at least in the past, not much reviewing, and regularly turned up on Beal’s predatory publishers lists.)

        1. Lane Simonian says:

          Thank you for pointing out that your skepticism is being applied to the journal in this case. Perhaps, the next linked journal is not particularly good either, but one can find several articles in several different journals where the authors reach similar conclusions.

          http://onlinelibrary.wiley.com/doi/10.1111/imm.12443/pdf

          I think that it is easier to say a disease is not well understood, then to say “our” approach to a disease (i.e. amyloid antibodies for Alzheimer’s disease or selective serotonin reuptake inhibitors for depression) is at least partially wrong. If you try a hundred different things and nothing works, then the disease is complicated; if you try the same thing a hundred times with the same results than the problem is not with the disease but with the people studying it.

          1. Ian Malone says:

            Nowhere near my field at all, so I can’t say for definite, but yes, I’d be inclined to put more stock in that as an established society journal, not pay to publish, and with editors at well known institutions who I can look up and who list being on the board on their own sites. Of course it’s not a guarantee every article there is going to be perfect, just as being in a Hinadwi title doesn’t mean something is going to be wrong (though in that case you tend to wonder why they couldn’t get it somewhere rigourous).

    1. The Lunatic says:

      Yet “linked to” doesn’t tell you bupkis. Does inflammation cause depression, does depression cause inflammation, are both symptoms of an underlying cause, or what?

      What we do know is that treatments for inflammation don’t work as anti-depressants, but yanking around neurotransmitters does.

  18. steve says:

    Oy. As an immunologist, I should add that inflammation involves a huge constellation of mediators – direct cell-cell interactions, antibodies, complement, cytokines, neuropeptides, prostaglandins, leukotrienes, thromboxanes, prostacyclins, exosomes, bradykinins, histamine, serotonin, clotting factors, fibrin products, nitric acid, vasoactive amines, platelet activating factor, proteolytic enzymes, fibrinopeptides, etc, etc. – besides ROS. If ROS were the be-all and end-all of inflammation then life would be simple indeed.

    1. Lane Simonian says:

      Yes, but there are critical ties between not only reactive oxygen species and reactive nitrogen species and inflammation via DNA damage, but also oxidative damage to receptors involved in mood (serotonin) and the recall of short-term memories (muscarinic acetylcholine). By altering various enzymes, reactive oxygen species and reactive nitrogen species can also tip the balance toward cell growth (cancer) or cell death (various neurodegenerative diseases). Reversing or partially reversing oxidative and nitrostative damage can potentially play a role in the treatment of a variety of diseases.

    2. Some idiot says:

      Re inflammation and depression: a very interesting point that I had not considered before. I have suffered both major depression plus a relapse after over a decade of being totally stable (and on medication). I am now stable again after a change in treatment. My sister had juvenile rheumatoid arthritis, which really ended up consuming her over the period of 30-40 years.

      One point does not of course make a correlation. However, have there been any studies linking patients with depression to other family members suffering from inflammation disorders? Thank you for your “food for thought”, Steve!

      1. steve says:

        Yes, there are quite a number of studies now about the link between depression and inflammation. For example, about one-third of healthy people treated with interferon develop depression, which indicates that inflammation is a cause, not a consequence. There are studies that show that people with depression that have high levels of circulating inflammatory markers (e.g., CRP) don’t respond to SSRIs. Lots to consider there but again, ROS is just a small fraction of the mediators that the immune system makes so it is likely to be more global than that.

        1. Some idiot says:

          Thanks! Wow, that interferon result is a bit of a wake-up call… interesting…

  19. John Finkbiner says:

    It could turn out to be something like “If you have more than X% of Type 473 neurons in subregion 79Q of the forebrain, you’re at risk for slipping into Alternate Neuronal Network Firing Patterns #2907 through 3043 if the balance of long-axon activity decreases, potentiating a feedback loop of protein synthesis that produces mixed-GPCR phenotypes #973 through 1028, spreading distally through axonal networks 384 through. . .”

    I have no expertise here except for having experienced a major depressive episode, but I suspect this is wrong. I think depression” is like “headache” Imagine going to a Doctor Who told you “you have headache. Some people react well to an antibiotic, and others improve from putting ice on their heads. Most people feel better after taking Tylenol, so let’s try that first.” Obviously the correct treatment depends on the cause — a sinus infection is different from a minor head trauma — but without a better understanding of the possible causes, the best you can do is try different treatments until something works. I think we will know we have made major progress in understanding depression when we have meaningful subcategories that can guide treatment.

    I don’t want to minimize the current treatments, by the way. I’m fairly sure I was periodically moderately depressed during most of middle and high school* and I’m certain I had a deep depression in college. Since I started the antidepressents** I have been fairly stable for more than 20 years.

    *Once I had experienced unequivocal depression I realized I had had similar but less severe symptoms for years. It’s not easy to study something when you can’t reliably tell whether it’s present.

    **Really it was about a year after I found a cocktail of drugs that worked that I felt confident I was back to normal.

  20. Feling Better says:

    No argument that the MoA for many antidepressants is not well understood. That said, there is begining to be a greater understanding of cellular responses to many compounds in the class of rapid acting antidepressants where postsynaptic activation of mTORC1 and subsequent increases in the synthesis of key synaptic signaling proteins and BDNF lead to long term synaptic remodeling which has been linked to mood modulation and symptom releif.

    http://www.eurekaselect.com/140313/article
    https://www.sciencedirect.com/science/article/pii/S0028390813002517?via%3Dihub
    http://onlinelibrary.wiley.com/doi/10.1111/bcp.12845/abstract;jsessionid=6C4A6D195947E7160926BDCC5D855486.f02t04

  21. woodstock says:

    A couple of things that I am surprised no one has mentioned in the comments yet:

    1. Ketamine, an NMDA receptor antagonist (at very least), has shown surprisingly positive results in clinical trials, including a recent phase 2 result:

    https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2666767?resultClick=1

    Unlike a lot of anti-depressants, ketamine works fast (hours). This certainly has to be saying something about the molecular mechanism of depression.

    2. On the inflammatory side (and on the oxidative stress side), I feel there are far too many studies where researchers look at a large panel of inflammatory markers and draw strong conclusions when they see one or two markers significantly (weasel word) different in patients versus controls. Unfortunately, given a large enough set of variables, one can always find statistical correlations, which may or may not have any meaning. Validation requires prospective studies using independent groups of patients (as well as good MOA studies). I don’t see these as often as I would like.

    On the other hand, the antibody drug brodalumab, which targets the inflammatory cytokine receptor IL-17 has been shown to induce strong suicidal ideation in patients in multiple clinical trials. So clearly there is an inflammation-mood link.

    3. Finally, we (well, I) tend to consider effective depression therapies such as talk therapy (CBT) and ECT as distinct from molecular therapies. But clearly, they have to ultimately be working on a molecular-cellular level. And CBT and anti-depressants can be synergistic, so clearly there is something to be learned here. I am just not sure what.

    1. steve says:

      I don’t think you’re very familiar with the work on inflammation and depression; if you are then your characterization sure doesn’t reflect that knowledge. Thirty percent of people given interferon develop depression when they never had a history of it. Flare ups of inflammatory diseases like RA, MS, etc. are associated with depression. You can predict which patients will respond to SSRIs by measuring circulating serum markers – high levels of IL-1β, IL-6, TNF-α , IFN-γ are found in patients who don’t respond. The literature on inflammation and depression is robust and much better documented than that relating serotonin levels to depressive episodes.

      1. woodstock says:

        Thanks Steve. I’m not familiar with the literature you mentioned. That does seem pretty compelling although I wonder how much of the depression with RA and MS is due to the disease and how much is due to the treatment.

        I still stand by my statement that the literature has a lot of studies looking at panels of inflammatory markers and making correlations that are meaningless. The treatment-related effects you are more interesting although many reviews and meta-analyses still seem quite skeptical.

        1. NJBiologist says:

          I thought the same thing about the RA/MS hypothesis, woodstock.

          Also, I’m hesitant about the interferon results… seems like something that nonspecifically reduces translation could easily be having some non-immune effects.

    2. Lane Simonian says:

      That NMDA receptor antagonists may have a role in treating depression is interesting since the NMDA receptor plays a major role in neurodegenerative diseases as part of a pathway leading to oxidation and inflammation. Here is a possible alternative to ketamine.

      https://www.frontiersin.org/articles/10.3389/fpsyt.2015.00172/full

      The conclusion from this article may also be worth considering:

      A review on the oxidative and nitrosative stress (O&NS) pathways in major depression and their possible contribution to the (neuro)degenerative processes in that illness

      “This paper reviews the pathways by which lowered antioxidants and O&NS may contribute to depression, and the (neuro)degenerative processes that accompany that illness. It is concluded that aberrations in O&NS pathways are – together with the inflammatory processes – key components of depression. All in all, the results suggest that depression belongs to the spectrum of (neuro)degenerative disorders.”

      https://www.sciencedirect.com/science/article/pii/S0278584610001776

      I don’t think it is an either/or proposition. Some forms of major depression at least may result from oxidative damage to serotonergic receptors, inflammatory damage to brain tissue, and the apoptosis of neurons.

  22. If your watch shows always a wrong reading of the time as a FUNCTION of the correct time, if you put your fingers into it and screw it, whatever the theory you had in mind, you will get the correct time every 12h.

  23. Bacillus says:

    Regarding the mode of action of anaesthetics. Many (all?) of them seem to work on many mammalian species including mice. Literally thousands of mutant mice have already been generated with many thousands more to come. If anaesthetics have an absoute requirement for a particular receptor in order to work, then anaesthesia-resistant mice may soon be generated. In fact they may already exist, but no one has screened them for this particular trait. Along similar lines, are there any reports in the medical literature of patients who required significantly more anaesthesia than normal to render them unconscious?

  24. steve says:

    Bacillus – When I was a post-doc purifying cytokines, a post-doc from another lab came and asked my advice on problems she was having purifying the factor responsible for tumor killing from her lab’s macrophages. She never could get a clean peak of the activity she was trying to purify no matter what column she used; it seemed to distribute randomly across fractions. We discussed different types of gradients, fractionation protocols, etc but nothing ever worked. Frustrated she move to another lab. Years later I read that the lab where she worked had demonstrated that the factor was nitric oxide. We’d always just assumed it was a protein like TNF.

    Don’t assume that anesthetics work through a receptor. They could well be having general effects on membrane properties, etc. As we’ve often seen in certain responses over the years to discussions in this column, when you have a hammer you think everything is a nail. The fact is, though, that there is more to biology than is dreamt of in our philosophies.

    1. tangent says:

      How do people square the “general futzing with membranes” theory with the chiral behavior of etomidate, or with flurothyl looking so darn antagonist-y?

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