This post is in response to Erik Hoel ’s post, “If serotonin isn't linked to depression, why do SSRIs even work?” on The Intrinsic Perspective (requires subscription). These issues require some detailed clarification, are of general interest, and have been coming up in discussions quite a bit over the past year, so I’ll address them here.
Thanks for writing this up, it was an interesting read! A couple points:
(a) Are you sure that electroshock therapy could not be described as a "random" perturbation? (with randomness, as I said originally, not meaning statistical white noise, just like untargeted perturbations that don't have anything to do with the etiology)
(b) Are you sure that trepanations were indeed never performed in medieval times, only fantasized about? Here's from Wikipedia (which may be wrong about this, but it seems pretty confident and links sources) https://en.wikipedia.org/wiki/Trepanning
"Hippocrates gave specific directions on the procedure from its evolution through the Greek age, and Galen also elaborates on the procedure. During the Middle Ages and the Renaissance, trepanation was practiced as a cure for various ailments, including seizures and skull fractures. Out of eight skulls with trepanations from the 6th to 8th centuries found in southwestern Germany, seven skulls show clear evidence of healing and survival after trepanation, suggesting that the survival rate of the operations was high and the infection rate was low.[4] . . .
During the 16th and 17th centuries, around 80% of people survived the procedure of trepanation.[8]"
I suppose one could lean on the notion that "various ailments" don't include any mental disorders, but I'd be interested in more about the history of it.
1) The challenge with ECT is that it produces a generalized seizure and no hypothesized mechanisms of action has yet generated consensus. Does ECT produce random perturbations? Yes, it does, cause of the generalized seizure, but it's another thing to show that the perturbations caused the benefit. If you look at other neuromodulatory interventions, such as transcranial magnetic stimulation or deep brain stimulation, it become evident very quickly that randomly stimulating the brain doesn't work; the stimulation has to be targeted to certain areas.
2) Sorry, I should have clarified that. I meant that there is no solid historical evidence that trepanation was used to treat mental illness. Trepanation was definitely used for other medical and neurological ailments.
Jan 26, 2023·edited Jan 26, 2023Liked by Awais Aftab
Just to quickly respond:
1) Hmm, I don't understand "it's another thing to show that the perturbations caused the benefit." Couldn't we say this about essentially anything at all? Why discount the evidence from ECT? I also doubt that DBS is actually as targeted as you describe - stimulation spreads out in the brain quickly. It is, after all, its purpose. You can TMS people at totally safe levels and watch the signal bounce back and forth across the entire cortex. And, just like everything else in neuroscience, the effect sizes will get smaller over time. I wouldn't be surprised if eventually DBS had about the same effectiveness on treatments of depression as ECT (imo, pretty minimal, but existent).
2) Interesting. It must be a widespread misunderstanding, as many online sources say it was used to treat "madness." Most do not have good sources though.
Feel free to have the last word on this one, as I'm interested in your thoughts on (1)
I'm not discounting ECT. I'm just saying that ECT does a lot of different things in the brain and it's difficult to say what accounts for the benefit. Traditional hypotheses have focused on the effects of ECT on neurotransmitters, neurogenesis and neuroplasticity, hormones, brain metabolism, and functional connectivity. Is it possible that ECT works by generalized, non-specific perturbation of brain functioning? Possibly, I have no way of refuting that, but ECT effect itself doesn't discriminate between various competing hypothesis. (Interestingly, my understanding is that epileptic seizures don't confer the same benefits on depression but ECT does. I don't have a handy reference for that, but *if* that is true, that might go against generalized nonspecific perturbation.)
It is true that with DBS the activation spreads, but the therapeutic benefit is only associated with certain sorts of activation. For example, Conroy and Holtzheimer wrote in 2019: "it has become increasingly clear that targeting and activating particular white matter tracts in each individual patient is likely critical in treatment response. I.e., gross anatomic targeting alone is probably not sufficient. For the SCC, this was first suggested via a retrospective analysis, using activation volume tractography, in which DBS responders shared bilateral activation pathways from SCC to frontal regions, cingulate cortex, and subcortical regions. Non-responders did not show consistent activation pathways in all these regions" (https://www.sciencedirect.com/science/article/pii/S2468171719300134 )
For TMS, dorsolateral prefrontal cortex has been the traditionally favored site of stimulation cause it demonstrate efficacy. But why this site and not others? If we are merely hoping for a random perturbation, why should DLPFC show better results than any other brain region which we could stimulate using TMS?
I think you are on to something with the toy hypothesis. But it probably needs to be refined further: the perturbation doesn't have to be linked to etiology, but it likely needs to take place in a brain system/network that is mechanistically relevant to the symptomatic state. As I mentioned, I suspect symptom network approaches align with this sort of thinking, because we can disrupt a network or a feedback loop with many different, even seemingly random, interventions.
"Serotonergic system or even serotonergic alterations may be involved in depression in some complex manner, but depression is a highly heterogenous and multifactorial condition, and involves a range of neurophysiological, psychological, and sociopolitical factors."
The general public's perennial fixation on serotonin--exacerbated by Big Pharma ads and the misleading and muddled "umbrella review" by Moncrieff et al--is partly a consequence of inadequate "messaging" by professional psychiatric organizations and academic psychiatry. All of us (including this writer) could have done a better job in communicating to the public the vast heterogeneity of "depression" and the immense complexity of neurobiological, psychological and sociocultural factors in its genesis. And all of this is aside from the well-established, albeit modest, efficacy of antidepressants in treating at least a significant subgroup of patients with major depression.
Not incidentally, it is worth noting that the whole notion of "serotonergic" antidepressants is misleading to begin with. Sertraline, for example, also affects reuptake of dopamine, while paroxetine has effects on norepinephrine. [see, e.g., Richelson E, J Clin Psychiatry 64 (suppl 13)5-12, 2003). Finally, of course, the antidepressant bupropion [Wellbutrin] has almost no effect on serotonin--it enhances noradrenergic and dopaminergic function--and yet is an effective agent in depression. All this has been known for many years, but was never fully explained to clinicians or the general public.
Most likely--and somewhat ironically--these neurotransmitter effects are largely a "sideshow" vis-a-vis the proximate mechanism of action of most antidepressants, which probably involves enhanced expression of neurotrophic factors like BDNF and enhanced "signalling" among neural networks.
Dr. George Dawson and I explore these issues in detail in Psychiatric Times, and companion pieces by Dr. Alexander Lisinski and me explore the issue of antidepressant efficacy. The links follow, FYI.
Sorry, the first two links are to the same article. I had intended to cite this one, which briefly discusses mechanisms of action, and debunks the "emotional blunting" claim for antidepressant action:
I really appreciate you bringing up that serotonin isn't necessarily the cause of depression. This is a really important point, especially when you consider that elevated (not normal) levels of serotonin are a major cause of health problems potentially including cancer.
Thanks for writing this up, it was an interesting read! A couple points:
(a) Are you sure that electroshock therapy could not be described as a "random" perturbation? (with randomness, as I said originally, not meaning statistical white noise, just like untargeted perturbations that don't have anything to do with the etiology)
(b) Are you sure that trepanations were indeed never performed in medieval times, only fantasized about? Here's from Wikipedia (which may be wrong about this, but it seems pretty confident and links sources) https://en.wikipedia.org/wiki/Trepanning
"Hippocrates gave specific directions on the procedure from its evolution through the Greek age, and Galen also elaborates on the procedure. During the Middle Ages and the Renaissance, trepanation was practiced as a cure for various ailments, including seizures and skull fractures. Out of eight skulls with trepanations from the 6th to 8th centuries found in southwestern Germany, seven skulls show clear evidence of healing and survival after trepanation, suggesting that the survival rate of the operations was high and the infection rate was low.[4] . . .
During the 16th and 17th centuries, around 80% of people survived the procedure of trepanation.[8]"
I suppose one could lean on the notion that "various ailments" don't include any mental disorders, but I'd be interested in more about the history of it.
Thanks Erik!
1) The challenge with ECT is that it produces a generalized seizure and no hypothesized mechanisms of action has yet generated consensus. Does ECT produce random perturbations? Yes, it does, cause of the generalized seizure, but it's another thing to show that the perturbations caused the benefit. If you look at other neuromodulatory interventions, such as transcranial magnetic stimulation or deep brain stimulation, it become evident very quickly that randomly stimulating the brain doesn't work; the stimulation has to be targeted to certain areas.
2) Sorry, I should have clarified that. I meant that there is no solid historical evidence that trepanation was used to treat mental illness. Trepanation was definitely used for other medical and neurological ailments.
Just to quickly respond:
1) Hmm, I don't understand "it's another thing to show that the perturbations caused the benefit." Couldn't we say this about essentially anything at all? Why discount the evidence from ECT? I also doubt that DBS is actually as targeted as you describe - stimulation spreads out in the brain quickly. It is, after all, its purpose. You can TMS people at totally safe levels and watch the signal bounce back and forth across the entire cortex. And, just like everything else in neuroscience, the effect sizes will get smaller over time. I wouldn't be surprised if eventually DBS had about the same effectiveness on treatments of depression as ECT (imo, pretty minimal, but existent).
2) Interesting. It must be a widespread misunderstanding, as many online sources say it was used to treat "madness." Most do not have good sources though.
Feel free to have the last word on this one, as I'm interested in your thoughts on (1)
I'm not discounting ECT. I'm just saying that ECT does a lot of different things in the brain and it's difficult to say what accounts for the benefit. Traditional hypotheses have focused on the effects of ECT on neurotransmitters, neurogenesis and neuroplasticity, hormones, brain metabolism, and functional connectivity. Is it possible that ECT works by generalized, non-specific perturbation of brain functioning? Possibly, I have no way of refuting that, but ECT effect itself doesn't discriminate between various competing hypothesis. (Interestingly, my understanding is that epileptic seizures don't confer the same benefits on depression but ECT does. I don't have a handy reference for that, but *if* that is true, that might go against generalized nonspecific perturbation.)
It is true that with DBS the activation spreads, but the therapeutic benefit is only associated with certain sorts of activation. For example, Conroy and Holtzheimer wrote in 2019: "it has become increasingly clear that targeting and activating particular white matter tracts in each individual patient is likely critical in treatment response. I.e., gross anatomic targeting alone is probably not sufficient. For the SCC, this was first suggested via a retrospective analysis, using activation volume tractography, in which DBS responders shared bilateral activation pathways from SCC to frontal regions, cingulate cortex, and subcortical regions. Non-responders did not show consistent activation pathways in all these regions" (https://www.sciencedirect.com/science/article/pii/S2468171719300134 )
For TMS, dorsolateral prefrontal cortex has been the traditionally favored site of stimulation cause it demonstrate efficacy. But why this site and not others? If we are merely hoping for a random perturbation, why should DLPFC show better results than any other brain region which we could stimulate using TMS?
I think you are on to something with the toy hypothesis. But it probably needs to be refined further: the perturbation doesn't have to be linked to etiology, but it likely needs to take place in a brain system/network that is mechanistically relevant to the symptomatic state. As I mentioned, I suspect symptom network approaches align with this sort of thinking, because we can disrupt a network or a feedback loop with many different, even seemingly random, interventions.
Thanks for making this critical point, Awais:
"Serotonergic system or even serotonergic alterations may be involved in depression in some complex manner, but depression is a highly heterogenous and multifactorial condition, and involves a range of neurophysiological, psychological, and sociopolitical factors."
The general public's perennial fixation on serotonin--exacerbated by Big Pharma ads and the misleading and muddled "umbrella review" by Moncrieff et al--is partly a consequence of inadequate "messaging" by professional psychiatric organizations and academic psychiatry. All of us (including this writer) could have done a better job in communicating to the public the vast heterogeneity of "depression" and the immense complexity of neurobiological, psychological and sociocultural factors in its genesis. And all of this is aside from the well-established, albeit modest, efficacy of antidepressants in treating at least a significant subgroup of patients with major depression.
Not incidentally, it is worth noting that the whole notion of "serotonergic" antidepressants is misleading to begin with. Sertraline, for example, also affects reuptake of dopamine, while paroxetine has effects on norepinephrine. [see, e.g., Richelson E, J Clin Psychiatry 64 (suppl 13)5-12, 2003). Finally, of course, the antidepressant bupropion [Wellbutrin] has almost no effect on serotonin--it enhances noradrenergic and dopaminergic function--and yet is an effective agent in depression. All this has been known for many years, but was never fully explained to clinicians or the general public.
Most likely--and somewhat ironically--these neurotransmitter effects are largely a "sideshow" vis-a-vis the proximate mechanism of action of most antidepressants, which probably involves enhanced expression of neurotrophic factors like BDNF and enhanced "signalling" among neural networks.
Dr. George Dawson and I explore these issues in detail in Psychiatric Times, and companion pieces by Dr. Alexander Lisinski and me explore the issue of antidepressant efficacy. The links follow, FYI.
https://www.psychiatrictimes.com/view/the-serotonin-fixation-much-ado-about-nothing-new
https://www.psychiatrictimes.com/view/serotonin-or-not-antidepressants-work
https://www.psychiatrictimes.com/view/antidepressants-placebos-and-lithium-some-parting-thoughts
https://www.psychiatrictimes.com/view/hooked-on-hype-a-critical-examination-of-recent-anti-antidepressant-reporting
Best regards,
Ron
Ronald W. Pies, MD
Sorry, the first two links are to the same article. I had intended to cite this one, which briefly discusses mechanisms of action, and debunks the "emotional blunting" claim for antidepressant action:
https://www.psychiatrictimes.com/view/antidepressants-do-not-work-by-numbing-emotions
Regards,
Ron
I really appreciate you bringing up that serotonin isn't necessarily the cause of depression. This is a really important point, especially when you consider that elevated (not normal) levels of serotonin are a major cause of health problems potentially including cancer.
https://mattcook.substack.com/p/happy-to-horrified-the-lies-of-serotonin