signal to noise ratio of sum score outcomes in psychopharmacology research is just too high to really take effect size magnitudes literally. do you really interpret them quantitatively, i.e. "augmentation leads to 0.3 SD less depression? I usually take it as a qualitative hint, i.e. it works in general and is a good idea to try or not. Maybe ordinal ranking is feasible but even that is hard former (thinking of Cipriani)
I try and at least understand what effect sizes mean quantitatively, because that helps me understand if the mean effect even looks vaguely like it has clinical significance. I've warmed up to a lot of vague-but-about-function scales like the CGI for this reason. I try to avoid using effect sizes as a qualitative hint from the start because I think psychiatry is filled with too many small/small-medium effect sizes that translate into borderline meaningless benefits (e.g. an additional improvement of 2 points on something like the HAM-D, woo)
Leucht has some good papers like "What does the PANSS mean?" or "What does the MADRS mean?" that I think have been helpful in refining my thinking and acting as a reference point.
Very good piece, but I still feel that doing clinical trials on “MDD” is about as useful as doing the same for “fever.” Why would we expect good results?
I tend to agree, though the question is what construct do we replace it with? My (admittedly more shallow than I'd like) impression is that attempts to find subgroups of patients diagnosed with MDD with distinct patterns of response has not been terribly fruitful.
I am a fan of the idea of dimensional models like HiTOP, though I think that will just lead us to a purely symptom-driven approach. Maybe that's what we want, but it doesn't seem like it will be terribly different than what we're currently doing!
I had not heard of Ban before, though reading what you linked and going down the rabbit hole of Wernicke–Kleist–Leonhard nosology, I am sorry that I am just learning about it now. Thank you very much for sharing!
The Astrup and Fish paper is certainly interesting, but I probably don't need to point out that it is not blinded, dose controlled, etc. etc. so there is an enormous potential for bias in this study. I don't think we can take it at face value as something that works, but I do think it could be valuable to try and do some modern studies using these subtypes and see what falls out!
We also have to content with studies like this one (https://www.nature.com/articles/s41380-019-0502-5) that suggest that there are not unique subgroups of psychotic individuals who respond differentially to treatment.
I agree the study needs follow-up, but I’m not sure an RCT would answer the same questions. This study isn’t trying to measure the statistical significance of a modest or marginal effect; it’s looking at whether there are differences in treatment response between relatively homogeneous clinical subgroups that are large enough to be obvious without statistics. It’s essentially an interocular trauma test. It’s not looking for a three-point change on a fifty-point scale. In this case they identified entire diagnostic groups that show no meaningful response to any of the drugs. That kind of finding is groundwork that arguably needs to happen before RCTs, not after. It’s separating the wheat from the chaff, looking for the large pieces that split away easily.
The WLK is interesting, as is much of the old German literature. That isn’t to say I think Leonhard was right nor Kleist. He was certainly eccentric and arguably got into counting angels on the head of a pin. Fish's study suggests he overshot the mark on his divisions by quite a margin. However, it also demonstrates that "over-splitting" could be experimentally useful, and that "the attempt" to carve diseases at their joints might be almost as good as the real thing if you're willing to be meticulous. Psychiatry often complains that its categories are too heterogeneous for research purposes; this work shows that deliberately creating more homogeneous groups, even when etiology is uncertain, could help triangulate the true underlying substrate. I think the reason the DSM doesn’t achieve this same result is because it is splitting by committee and horse trading, whereas Leonhard is splitting by pedantry. Horse trading is not the same as counting angels on the heads of pins.
The study you linked to looks like GIGO to me at a glance. I'm not sure if g = 0.47 supports the authors conclusions, it seems consistent with heterogeneous groups and weak effect. Also, I'm not sure if there is a serious scientific question about the existence of a non-responsive group. I mean, it's sort of logically impossible, you only need a handful of people to demostrate the existence of non-response. I suppose non-response raises diagnostic questions but how do you have no non-responder groups? Its sort of extraodinary. That is just off the top of my head though. Actually it makes me think of that Mitchell and Webb sketch "Can People Levitate?". It just seems... like I bet if I read each of the 30 studies individually it would quickly become obvious that the conclusion of the meta-analysis is logically impossible. I could be wrong though, and I'm definately being lazy, but I'm actually taking my first unit of statistics right now and I'm supposed to be doing an assignment, so I'll just assume I'm wrong about this since I only had time to read the abstract.
This may be your best writing yet Nils! Based on some of the polls Scott has posted previously, I would not be surprised if most MDs lack the statistical knowledge to correctly interpret this study as you have done. It also seems completely wild to me to assume Mirtazapine is just an "a2 antagonist" and pharmacological equivalent to trazadone and others. From my understanding, Mirtazapine has similar affinity for 5HT2a
Thanks kev; this is the first one I've written in a while that I'm proud of. It's very satisfying to teach yourself something and then understand it well enough to translate it into (relatively) less technical language.
I think that it was fair for the authors to put together mianserin and mirtazapine together - they're pretty similar drugs from a receptor-affinity point of view. The inclusion of trazodone is most baffling to me given that it has direct effects at SERT.
The complete normalisation of the mass labelling and drugging of children and adults has got to be Psychiatries most destructive era yet. Given its history thats really saying something.
Idk about you but I’d much rather people get handed SSRIs — which they have the choice to decline — than get absolutely tanked from the get go on clomipramine. The era of routine lobotomization and dehumanization was clearly worse, get some perspective.
Get some perspective, ok. By the way, we are still hacking into brains and blasting them with ECT today. While obviously brutal and insane, even at its peak lobotomy and related brutal madness, only managed to brain damage tens of thousands. However, in the modern era we are mislabelling with a range of DSM twaddle and drugging tens of millions of children and adults the world over on the back of these erroneous labels.
The damage to human health is incalculable. So many drugs are now prescribed that the unmetabolized junk being urinated out into rivers and seas is changing the behaviour of marine life.
Lobotomies for intractable seizures and ECT for profound treatment-resistant depression are lifelines for people who would otherwise be crippled interminably by organic disease. For the vast majority of the “tens of millions” you’re talking about, the sum total of these “incalculable” negative effects are basically feeling a little off on SSRIs, dealing with the (admittedly often very unpleasant) withdrawal syndromes of something like an Effexor, or not being able to get your dick hard. It takes a whole lot of ignoring what your eyes can very clearly see to think that the effects of these medications approach anything resembling “drugging”.
I am trying to work out if the ignorance in your comment is just ignorance or wilful ignorance? The negative effects are many, varied and catastrophic, hence my wondering about your ignorance. To minimise the significance of sexual dysfunction is ignorance in action. I suggest you go explore than many ‘survivor’ groups and support services for people harmed and often killed by the impact of these drugs. Its amazing to me that terms like ‘antidepressants’ and ‘SSRI’s are both misleading. The first is purely a marketing term based on corrupt research and the latter another untruth. These drugs have wide ranging effects across the body and brain and no one really knows exactly what they are doing because no one has bothered to do detailed long term studies.
signal to noise ratio of sum score outcomes in psychopharmacology research is just too high to really take effect size magnitudes literally. do you really interpret them quantitatively, i.e. "augmentation leads to 0.3 SD less depression? I usually take it as a qualitative hint, i.e. it works in general and is a good idea to try or not. Maybe ordinal ranking is feasible but even that is hard former (thinking of Cipriani)
I try and at least understand what effect sizes mean quantitatively, because that helps me understand if the mean effect even looks vaguely like it has clinical significance. I've warmed up to a lot of vague-but-about-function scales like the CGI for this reason. I try to avoid using effect sizes as a qualitative hint from the start because I think psychiatry is filled with too many small/small-medium effect sizes that translate into borderline meaningless benefits (e.g. an additional improvement of 2 points on something like the HAM-D, woo)
Leucht has some good papers like "What does the PANSS mean?" or "What does the MADRS mean?" that I think have been helpful in refining my thinking and acting as a reference point.
Very good piece, but I still feel that doing clinical trials on “MDD” is about as useful as doing the same for “fever.” Why would we expect good results?
I tend to agree, though the question is what construct do we replace it with? My (admittedly more shallow than I'd like) impression is that attempts to find subgroups of patients diagnosed with MDD with distinct patterns of response has not been terribly fruitful.
I am a fan of the idea of dimensional models like HiTOP, though I think that will just lead us to a purely symptom-driven approach. Maybe that's what we want, but it doesn't seem like it will be terribly different than what we're currently doing!
Have you Tom Bans's idea about “homotyping”? It worked for Astrup and Fish.
a-neuropszichofarmakologiai-kutatas-klinikai-modszereirl.pdf https://share.google/oMUYVbCMX6dQI0ili
The response of the different Leonhard subgroups of schizophrenia of psychotropic drugs https://share.google/2NgCU8iNfM8P0hPoH
I had not heard of Ban before, though reading what you linked and going down the rabbit hole of Wernicke–Kleist–Leonhard nosology, I am sorry that I am just learning about it now. Thank you very much for sharing!
The Astrup and Fish paper is certainly interesting, but I probably don't need to point out that it is not blinded, dose controlled, etc. etc. so there is an enormous potential for bias in this study. I don't think we can take it at face value as something that works, but I do think it could be valuable to try and do some modern studies using these subtypes and see what falls out!
We also have to content with studies like this one (https://www.nature.com/articles/s41380-019-0502-5) that suggest that there are not unique subgroups of psychotic individuals who respond differentially to treatment.
I agree the study needs follow-up, but I’m not sure an RCT would answer the same questions. This study isn’t trying to measure the statistical significance of a modest or marginal effect; it’s looking at whether there are differences in treatment response between relatively homogeneous clinical subgroups that are large enough to be obvious without statistics. It’s essentially an interocular trauma test. It’s not looking for a three-point change on a fifty-point scale. In this case they identified entire diagnostic groups that show no meaningful response to any of the drugs. That kind of finding is groundwork that arguably needs to happen before RCTs, not after. It’s separating the wheat from the chaff, looking for the large pieces that split away easily.
The WLK is interesting, as is much of the old German literature. That isn’t to say I think Leonhard was right nor Kleist. He was certainly eccentric and arguably got into counting angels on the head of a pin. Fish's study suggests he overshot the mark on his divisions by quite a margin. However, it also demonstrates that "over-splitting" could be experimentally useful, and that "the attempt" to carve diseases at their joints might be almost as good as the real thing if you're willing to be meticulous. Psychiatry often complains that its categories are too heterogeneous for research purposes; this work shows that deliberately creating more homogeneous groups, even when etiology is uncertain, could help triangulate the true underlying substrate. I think the reason the DSM doesn’t achieve this same result is because it is splitting by committee and horse trading, whereas Leonhard is splitting by pedantry. Horse trading is not the same as counting angels on the heads of pins.
The study you linked to looks like GIGO to me at a glance. I'm not sure if g = 0.47 supports the authors conclusions, it seems consistent with heterogeneous groups and weak effect. Also, I'm not sure if there is a serious scientific question about the existence of a non-responsive group. I mean, it's sort of logically impossible, you only need a handful of people to demostrate the existence of non-response. I suppose non-response raises diagnostic questions but how do you have no non-responder groups? Its sort of extraodinary. That is just off the top of my head though. Actually it makes me think of that Mitchell and Webb sketch "Can People Levitate?". It just seems... like I bet if I read each of the 30 studies individually it would quickly become obvious that the conclusion of the meta-analysis is logically impossible. I could be wrong though, and I'm definately being lazy, but I'm actually taking my first unit of statistics right now and I'm supposed to be doing an assignment, so I'll just assume I'm wrong about this since I only had time to read the abstract.
I share your pessimism but I'm not sure there's any other option but to keep trying to sub-phenotype with new methods.
This may be your best writing yet Nils! Based on some of the polls Scott has posted previously, I would not be surprised if most MDs lack the statistical knowledge to correctly interpret this study as you have done. It also seems completely wild to me to assume Mirtazapine is just an "a2 antagonist" and pharmacological equivalent to trazadone and others. From my understanding, Mirtazapine has similar affinity for 5HT2a
Thanks kev; this is the first one I've written in a while that I'm proud of. It's very satisfying to teach yourself something and then understand it well enough to translate it into (relatively) less technical language.
I think that it was fair for the authors to put together mianserin and mirtazapine together - they're pretty similar drugs from a receptor-affinity point of view. The inclusion of trazodone is most baffling to me given that it has direct effects at SERT.
The complete normalisation of the mass labelling and drugging of children and adults has got to be Psychiatries most destructive era yet. Given its history thats really saying something.
Idk about you but I’d much rather people get handed SSRIs — which they have the choice to decline — than get absolutely tanked from the get go on clomipramine. The era of routine lobotomization and dehumanization was clearly worse, get some perspective.
Get some perspective, ok. By the way, we are still hacking into brains and blasting them with ECT today. While obviously brutal and insane, even at its peak lobotomy and related brutal madness, only managed to brain damage tens of thousands. However, in the modern era we are mislabelling with a range of DSM twaddle and drugging tens of millions of children and adults the world over on the back of these erroneous labels.
The damage to human health is incalculable. So many drugs are now prescribed that the unmetabolized junk being urinated out into rivers and seas is changing the behaviour of marine life.
Lobotomies for intractable seizures and ECT for profound treatment-resistant depression are lifelines for people who would otherwise be crippled interminably by organic disease. For the vast majority of the “tens of millions” you’re talking about, the sum total of these “incalculable” negative effects are basically feeling a little off on SSRIs, dealing with the (admittedly often very unpleasant) withdrawal syndromes of something like an Effexor, or not being able to get your dick hard. It takes a whole lot of ignoring what your eyes can very clearly see to think that the effects of these medications approach anything resembling “drugging”.
I am trying to work out if the ignorance in your comment is just ignorance or wilful ignorance? The negative effects are many, varied and catastrophic, hence my wondering about your ignorance. To minimise the significance of sexual dysfunction is ignorance in action. I suggest you go explore than many ‘survivor’ groups and support services for people harmed and often killed by the impact of these drugs. Its amazing to me that terms like ‘antidepressants’ and ‘SSRI’s are both misleading. The first is purely a marketing term based on corrupt research and the latter another untruth. These drugs have wide ranging effects across the body and brain and no one really knows exactly what they are doing because no one has bothered to do detailed long term studies.
I really enjoyed the statistics overview in this essay! Fascinating. Thank you