I have been on Prozac for over 35 years. I am a high risk patient. About 20 years ago I did try to taper off and went into a deep depression. Since that time I’ve accepted the fact that Prozac keeps me from going into deep depression. However, a part of me would really like to not take any drug. But this might be my ego speaking. Prozac has seemed to work for me, but I do believe that my brain has been permanently altered. I wish there was some way of finding out if it has. I’m 75 now and I don’t plan on going off Prozac in my last 10 to 20 years of life. But your article is very interesting even though I don’t understand a lot of it. I will continue to talk to my psychiatrist about this, but he has felt that I need to continue taking Prozac. At this time, I agree with him. But I sure wish there was some way of knowing how the Prozac use of 35 years has altered my brain. Thank you for the information.
So the paper "When Do Physical Symptoms After Antidepressant Cessation Reflect Pharmacodynamic versus Non-pharmacodynamic Clinical Phenomena?" (J Clin Psychiatry 2026;87(4):26ac16648) was just referenced on doximity psychiatry feed. After commenting on it apparently needing 19 authors (at 106 words per author) and seeing it contain the claim:
“No known physiological mechanisms plausibly account for pharmacodynamically based “withdrawal” symptoms that arise de novo long after complete drug elimination has occurred,"
And they assert that all such effects are really due purely to returning symptoms, the nocebo effect, and somatization. Almost immediately afterwards, I saw this article posted. Since I find your argument persuasive and consistent with what I knew from almost two decades doing bench science research on the serotonin system, I had to make a comment about that claim and reference this post. Hope you don't mind.
Thank you for this, Michael! The opportunity to reach someone like yourself with such a deep knowledge of the serotonin system is exactly why I wanted to post this article on Substack rather than on an academic journal with far less reach. You’re about as well-suited as anyone I can think of to assess this article, and I’d welcome any feedback you have on it! Feel free to DM me
Hi Daniel and Michael - A key thing here, as alluded to at the end of my comment above, is that both pharmacological and - for want of a better word - functional mechanisms can and do often co-exist so it's rarely a case of symptoms/disorders being 'one or the other'. FND often grows from an underlying initial organic disorder, symptom or even brief 'physiological abberation' that could even be entirely normal/healthy but is 'latched onto' by the brain when in a state of body/health hypervigilence that is normal/adaptive during and after accidents & illness. I'm increasingly convinced that there is inherently and always a functional component to any and all symptoms as this reflects the processes in the brain where symptoms are 'constructed' from the sensory/other inputs to the brain and shaped by both internal and external models of what normal versus pathological experience and bodily function are. It's just a question of whether this necessary functional component becomes excessive or persists longer than the underlying pathology that caused it's initiation - so in a sense there's a failure of the systme to 'reset' and symptom experience is stuck in an attractor basin/Bayesian valley etc!
You are absolutely correct that pharmacological and functional mechanisms not only can co-exist, that they often do exist together. In many ways that was the objection I raised to the J Clin Psych paper. They were claiming it was all just due to residual symptoms, nocebo effects, and somatization because there was no possible pharmacological mechanism. I stated they "are no doubt involved in and may completely account for some cases. But the idea that there is no possible mechanism for an SSRI induced post-acute withdrawal syndrome and thus all such cases must be due to these factors simply does not hold up."
I think you are probably correct that there is a degree of a functional component as a normal response to accidents and illness. And I thank you for the Van den Bergh et al. Neuroscience and Biobehavioral Review paper. Its an interesting concept, enough so I wonder how “interoceptive differentiation training” would be approached in practice. I would add that medicine in general does not deal well with this concept and tends to divide people into 'real' and 'fakers' when this is neither accurate nor helpful.
Completely agree with this. And Tim, your perspective that functional elements may play a role in most or all symptoms broadly is a very interesting one and makes sense to me. Again, please DM me if you have thoughts about how to best integrate this perspective into withdrawal workup and management!
Great article Daniel - very interesting. What you are describing here with your 'dynamical systems perspective' is, in my view, almost certainly - at least in part - describing the same mechanisms that underlie both functional symptoms and placebo, and most pertinenty here, nocebo effects.
This was the key initial paper linking up functional neurological disorder (FND) symptoms, previously known as conversion disorder and way back as Hysteria, from Mark Edwards which with Friston and other expanded the Bayesian account of brain function to motor and sensory symptoms https://academic.oup.com/brain/article-lookup/doi/10.1093/brain/aws129.
Richard Brown and others had been developing similar psychological models to which these new 'computational' accounts, which are so convincing as they so readily map to obvious underlying neurobiological mechanistic processes, were added in this superb paper which broadens the theoretical framework to all bodily symptoms, so not just neurological ones, and made more explicit and detailed connections between the neurobiological, cognitive, psychological and even social processes that are so obviously bidirectionally interlinked - and inseparable- in the creation and resolution of symptoms over and above initial physical ('organic') causes. See this, in my view seminal, paper https://www.sciencedirect.com/science/article/pii/S0149763416304729?via%3Dihub which warrants multiple careful reads!
The REBUS/other potential models of the therapeutic action of psychedelics also overlap with these processes so it's not surprising that functional symptoms, and perhaps medication withdrawal effect - that are almost certainly at least in part and in some, but likely a significant proportion of, patients a nocebo response that is effectively the same as a functional symptom or syndrome. This of course can, and likely regularly does, occur on top of an underlying 'organic' ('pharmacological') withdrawal syndrome that triggers initial symptoms which can either continue or varyingly resolve with time, but the resolution of which is not noticed by either patient or clinician as the experience/continuation of symptoms is taken over by a 'functional' (dynamical systems!) process that is either further maintained, exacerbated or even the kernel for the development of other symptoms by a completely separate set of mechanisms and factors that can be modulated both in terms of prevention and treatment of often highly disabling symptoms!
Hi Tim, thanks for this very insightful comment and for linking those papers! I definitely agree that predictive processing could play an important role in many cases of withdrawal--the same way it plays a role in many bodily symptoms, as you've aptly highlighted. However, one of my goals in writing this article was to make the case that protracted and delayed-onset withdrawal can happen below the level of perceptual and cognitive machinery that PP plays out at. I think an account of protracted/delayed onset WD can be described at a lower level of description, ie at the level of the serotonin system itself, and that is the level at which I apply dynamical systems theory in this article. So while the PP mechanisms underlying expectancy effects can certainly play a role in many cases, I don't think they are *necessarily* involved in all or most cases, and a mechanistic account can be made at the level of the serotonin system.
But, I am a big fan of PP broadly and very much agree with its account of functional symptoms and expectancy effects (and also think it helps explain that such processes are not simply psychological or just "in the patient's head"), and I think it's important that we look for these effects in withdrawal cases routinely. I see that you've done a lot of work with FND, so if you have any ideas about how to integrate evaluating for such into withdrawal workup and management, please feel free to DM me!
I find it rather astonishing that, under an article carefully explaining the biological plausibility of protracted withdrawal, we get yet another suggestion that the underlying pharmacological disturbance has probably resolved and a functional process has taken over.
Where is the evidence for this transition, and how can we distinguish it from an unresolved physiological disturbance?
I think the paper you call seminal illustrates exactly what concerns me. It moves from the observation that we cannot consistently identify physiological causes for MUS to proposing erroneous perceptual inference as an explanation. That is a legitimate hypothesis, but what evidence supports it over physiological dysfunction we simply have not identified yet? And even if such mechanisms play a role, how much do they actually explain? All of the symptoms? Half? Ten percent? Without knowing their contribution, how can we tell whether we have explained the condition or merely identified one contributing factor?
Unexplained symptoms are an expected part of incomplete medical knowledge, not evidence for any particular explanation. Medical history is full of confident explanations for poorly understood conditions. Imagine how sophisticated our psychological models of stomach ulcers might have become had we continued refining them instead of discovering H. pylori.
Predictive processing itself is not the issue. But its application to MUS often seems to carry the authority of a tested explanation without having passed those tests.
This is not just an academic concern. Such explanations risk making us think we already understand a condition, discouraging further research into its biological causes. And down the line, they can become yet another version of "it's all in your head" with real consequences for patients.
Rather ironically, this recent review (Rethinking Predictive Processing, https://doi.org/10.1146/annurev-neuro-102124-031410) finds "inconsistent empirical evidence" for predictive processing. Apparently, inconsistent physiological evidence calls for an alternative explanation, while inconsistent evidence for that alternative calls for further refinement of the model.
How do people differentiate return of natural symptoms and delayed withdrawal? I believe many are like me and still have anxiety and depression even while on an ssri, so would that be a sign that return of symptoms on discontinuation is a reflection of an underlying default state? Maybe as well as withdrawal. I’ve tried to come off ssris a few times over the years and always had to go back on. Two of the times it all seemed like it was going well until the 6 month mark. I feel like 6 months was a time when something changed. Thanks for the article, the technicalities are over my head but I get the gist and do believe withdrawal syndromes must be possible. Sorry to hear about your journey w mirtazapine, hope you’re ok.
I do not think emergence of depression and anxiety worsening during a taper necessarily indicates relapse; that is a common misguided assumption, but part of what I tried to illustrate here is that serotonin dysregulation during tapering can produce dysregulated anxiety and mood without that representing relapse. And thank you for the condolences; I'm doing OK!
Brilliant, vital. Two thoughts: first, thank you for the gentle blade insertion re: how one should look broadly at institutions when considering the dearth of research on w/d. Second, you mention winnowing to people at high-risk people prior to w/d studies to enrich the sample and decrease the noise. Tricky, that, no? But I think there might be such a group, just based on clinical experience, viz people living with bipolarity, especially those already in a mixed state on an antidepressant. It seemed to me that nearly everyone in that group was highly vulnerable to withdrawal -- versus my primary care colleagues' experience, where so few had major problems that the PCPs didn't even routinely prescribe the lowest available dose (Phelps et al, 2025).
Thank you for your work, and this essay, and sorry to hear about what you've had to go through to learn about all this so directly. JP
Awesome! Instead of the 'Minimum Effective Concentration" (MEC) paradigm, which is appropriate for antibiotics, thinking of dynamical systems as the underlying abstractions enable new posology strategies.
Thanks, and thanks for posting these! These are very interesting, and further illustrate how much psychiatry could benefit from application of dynamical systems concepts. I’d be curious how much some of these concepts you mention could be applied at a lower level e.g. the serotonin system itself
You are welcome! The last paper cites some studies that report natural cycles for 5HT, DA, and NE receptors, which suggests that treatment effects may vary with an oscilating posology. Nice to revisit this manuscript almost 10 years later. We also designed an RCT to test this hypothesis, but I could not get funding at the time.
- Koulu, M., Saavedra, J. M., Potter, W. Z., & Linnoila, M. (1986). Circadian covariation of norepinephrine and serotonin in the locus coeruleus and dorsal raphe nucleus in the rat. Brain Research, 397, 353–358.
- Praschak-Rieder, N., Willeit, M., Wilson, A. A., Houle, S., & Meyer, J. H. (2008). Seasonal variation in human brain serotonin transporter binding. Archives of General Psychiatry, 65, 1072–1078.
- Matheson, G. J., Schain, M., Almeida, R., Lundberg, J., Cselényi, Z., Borg, J., Varrone, A., Farde, L., & Cervenka, S. (2015). Diurnal and seasonal variation of the brain serotonin system in healthy male subjects. NeuroImage, 112, 225–231.
- Gannon, R. L., & Millan, M. J. (2007). Evaluation of serotonin, noradrenaline and dopamine reuptake inhibitors on light-induced phase advances in hamster circadian activity rhythms. Psychopharmacology, 195, 325–332.
- Carlsson, A., Svennerholm, L., & Winblad, B. (1980). Seasonal and circadian monoamine variations in human brains examined post mortem. Acta Psychiatrica Scandinavica, 61, 75–85.
- Ferris, M. J., España, R. A., Locke, J. L., Konstantopoulos, J. K., Rose, J. H., Chen, R., & Jones, S. R. (2014). Dopamine transporters govern diurnal variation in extracellular dopamine tone. Proceedings of the National Academy of Sciences, 111, E2751–E2759.
Brilliantly written. I have had some of the same hypothesis regarding delayed onset withdrawal.
I, myself have experienced 7 failed tapers with my last reinstatement being completely unsuccessful. This was puzzling to me and has led me down a path of several years worth of research.
Interestingly enough, my mother and I also developed hyperkinesis and severe bile reflux from withdrawal which has been protracted for over a decade. So sorry to hear you are going through this as well. This has been utterly debilitating, but after 22 years trying to get off SSRIs, it’s profoundly satisfying seeing all of this being talked about.
Thank you! And I’m sorry to hear you and your mother have gone through this— that is interesting that you have both experienced this related to withdrawal. Feel free to DM me if you’d like to discuss further
This is one of the more careful mechanistic arguments I've seen. You never treat variables as some isolated part doing its work on its own, such that the patient is rendered an automaton. That is my primary critique against this field. And I I commend you on invoking hysteresis, that is, time-lagged variables. If I'd push on anything, it's where the agency ends up once you use biology language. You keep narrating the serotonergic system itself as THE THING that adapts — somewhat disconnected from the whole person whose sleep/stress/serotonin dynamics you yourself point to as relevant. The "landscape" you're describing isn't really the serotonin system's landscape on its own, it's shaped by a person's WHOLE embodied and environmental situation, which you gesture at without really folding it into systems theory. If anything that makes the mechanistic case stronger. But again, I will forever attack any atomist who reduces causes to anything "smaller" than a legal person. Give me caus-ers of causes, of give me nothing.
Thank you for this great and thoughtful read! I’m both a patient with depression and a pediatric NP who Rx’s these meds (and, after personal experience brought me greater knowledge more thoughtfully deprescribes these meds as well!
On Prozac 20mg for 4 years in my early 20’s… no issues stopping. On it again for 10 years and expected no issues tapering in my late 50’s and had an AWFUL time… ultimately it took over 2 years to get off this med the 2nd time… which was most unexpected, so, I chafe at the suggestions that much of withdrawal is a patient anticipating a difficult experience.
When it happened to me, I googled. And found the info that, even as an NP, I sadly did not know. I bought Maudsley. I bought 2 copies and gifted one to my own psych NP who also did not know. I’m fortunate that he believed and supported me, because I know this is sadly not true for all patients.
I now present on this… 2nd national conference coming up next month.
Like you, I share a bit of my own experience at the end, even though that feels vulnerable… because I do think those of us in the medical field who do so adds a bit of depth to it. So, thank you for sharing your own experience!
Thank you for the kind words. I’m glad you found this helpful, and I’m sorry you’ve had to learn about withdrawal the same way I have, ie through personal experience. That is great that you present on the topic now and spread awareness! If you have any links to your talks I’d love to check them out!
I’ll be speaking at APNA in Phoenix end of October. I also have a podcast episode written and accepted for a primary care peds podcast but do not yet know when it will record/release. I have two other conference abstracts out there I’m waiting to hear on.
This is a link to my talk at NAPNAP in Pittsburgh last March… it’s recorded but not free and a bit more to access it as they bundled it with a couple other talks.
And… first time I spoke about this which is super vulnerable as first half is talking about how I ended up on antidepressants and last half is talking about tapering
This is interesting but also quite terrifying. I was thinking of tapering from Venlafaxine, and this article might have given me enough anxiety that I probably still need Venlafaxine
That was not my intention! I don't think you should be scared away from tapering, and what I was trying to establish is that careful tapering, if indicated, can make the process much safer and more tolerable.
I understand. It's just, I'd been taking various antidepressants for 10 years, and Venlafaxine specifically for 1 year, and it's eerie to think about what it had done to my brain over that time.
I have been on Prozac for over 35 years. I am a high risk patient. About 20 years ago I did try to taper off and went into a deep depression. Since that time I’ve accepted the fact that Prozac keeps me from going into deep depression. However, a part of me would really like to not take any drug. But this might be my ego speaking. Prozac has seemed to work for me, but I do believe that my brain has been permanently altered. I wish there was some way of finding out if it has. I’m 75 now and I don’t plan on going off Prozac in my last 10 to 20 years of life. But your article is very interesting even though I don’t understand a lot of it. I will continue to talk to my psychiatrist about this, but he has felt that I need to continue taking Prozac. At this time, I agree with him. But I sure wish there was some way of knowing how the Prozac use of 35 years has altered my brain. Thank you for the information.
So the paper "When Do Physical Symptoms After Antidepressant Cessation Reflect Pharmacodynamic versus Non-pharmacodynamic Clinical Phenomena?" (J Clin Psychiatry 2026;87(4):26ac16648) was just referenced on doximity psychiatry feed. After commenting on it apparently needing 19 authors (at 106 words per author) and seeing it contain the claim:
“No known physiological mechanisms plausibly account for pharmacodynamically based “withdrawal” symptoms that arise de novo long after complete drug elimination has occurred,"
And they assert that all such effects are really due purely to returning symptoms, the nocebo effect, and somatization. Almost immediately afterwards, I saw this article posted. Since I find your argument persuasive and consistent with what I knew from almost two decades doing bench science research on the serotonin system, I had to make a comment about that claim and reference this post. Hope you don't mind.
Thank you for this, Michael! The opportunity to reach someone like yourself with such a deep knowledge of the serotonin system is exactly why I wanted to post this article on Substack rather than on an academic journal with far less reach. You’re about as well-suited as anyone I can think of to assess this article, and I’d welcome any feedback you have on it! Feel free to DM me
Hi Daniel and Michael - A key thing here, as alluded to at the end of my comment above, is that both pharmacological and - for want of a better word - functional mechanisms can and do often co-exist so it's rarely a case of symptoms/disorders being 'one or the other'. FND often grows from an underlying initial organic disorder, symptom or even brief 'physiological abberation' that could even be entirely normal/healthy but is 'latched onto' by the brain when in a state of body/health hypervigilence that is normal/adaptive during and after accidents & illness. I'm increasingly convinced that there is inherently and always a functional component to any and all symptoms as this reflects the processes in the brain where symptoms are 'constructed' from the sensory/other inputs to the brain and shaped by both internal and external models of what normal versus pathological experience and bodily function are. It's just a question of whether this necessary functional component becomes excessive or persists longer than the underlying pathology that caused it's initiation - so in a sense there's a failure of the systme to 'reset' and symptom experience is stuck in an attractor basin/Bayesian valley etc!
You are absolutely correct that pharmacological and functional mechanisms not only can co-exist, that they often do exist together. In many ways that was the objection I raised to the J Clin Psych paper. They were claiming it was all just due to residual symptoms, nocebo effects, and somatization because there was no possible pharmacological mechanism. I stated they "are no doubt involved in and may completely account for some cases. But the idea that there is no possible mechanism for an SSRI induced post-acute withdrawal syndrome and thus all such cases must be due to these factors simply does not hold up."
I think you are probably correct that there is a degree of a functional component as a normal response to accidents and illness. And I thank you for the Van den Bergh et al. Neuroscience and Biobehavioral Review paper. Its an interesting concept, enough so I wonder how “interoceptive differentiation training” would be approached in practice. I would add that medicine in general does not deal well with this concept and tends to divide people into 'real' and 'fakers' when this is neither accurate nor helpful.
Completely agree with this. And Tim, your perspective that functional elements may play a role in most or all symptoms broadly is a very interesting one and makes sense to me. Again, please DM me if you have thoughts about how to best integrate this perspective into withdrawal workup and management!
Great article Daniel - very interesting. What you are describing here with your 'dynamical systems perspective' is, in my view, almost certainly - at least in part - describing the same mechanisms that underlie both functional symptoms and placebo, and most pertinenty here, nocebo effects.
This was the key initial paper linking up functional neurological disorder (FND) symptoms, previously known as conversion disorder and way back as Hysteria, from Mark Edwards which with Friston and other expanded the Bayesian account of brain function to motor and sensory symptoms https://academic.oup.com/brain/article-lookup/doi/10.1093/brain/aws129.
Richard Brown and others had been developing similar psychological models to which these new 'computational' accounts, which are so convincing as they so readily map to obvious underlying neurobiological mechanistic processes, were added in this superb paper which broadens the theoretical framework to all bodily symptoms, so not just neurological ones, and made more explicit and detailed connections between the neurobiological, cognitive, psychological and even social processes that are so obviously bidirectionally interlinked - and inseparable- in the creation and resolution of symptoms over and above initial physical ('organic') causes. See this, in my view seminal, paper https://www.sciencedirect.com/science/article/pii/S0149763416304729?via%3Dihub which warrants multiple careful reads!
This paper nicely summarises the overlap between functional symptoms and placebo/nocebo https://www.nature.com/articles/s41582-022-00711-z.
The REBUS/other potential models of the therapeutic action of psychedelics also overlap with these processes so it's not surprising that functional symptoms, and perhaps medication withdrawal effect - that are almost certainly at least in part and in some, but likely a significant proportion of, patients a nocebo response that is effectively the same as a functional symptom or syndrome. This of course can, and likely regularly does, occur on top of an underlying 'organic' ('pharmacological') withdrawal syndrome that triggers initial symptoms which can either continue or varyingly resolve with time, but the resolution of which is not noticed by either patient or clinician as the experience/continuation of symptoms is taken over by a 'functional' (dynamical systems!) process that is either further maintained, exacerbated or even the kernel for the development of other symptoms by a completely separate set of mechanisms and factors that can be modulated both in terms of prevention and treatment of often highly disabling symptoms!
Hi Tim, thanks for this very insightful comment and for linking those papers! I definitely agree that predictive processing could play an important role in many cases of withdrawal--the same way it plays a role in many bodily symptoms, as you've aptly highlighted. However, one of my goals in writing this article was to make the case that protracted and delayed-onset withdrawal can happen below the level of perceptual and cognitive machinery that PP plays out at. I think an account of protracted/delayed onset WD can be described at a lower level of description, ie at the level of the serotonin system itself, and that is the level at which I apply dynamical systems theory in this article. So while the PP mechanisms underlying expectancy effects can certainly play a role in many cases, I don't think they are *necessarily* involved in all or most cases, and a mechanistic account can be made at the level of the serotonin system.
But, I am a big fan of PP broadly and very much agree with its account of functional symptoms and expectancy effects (and also think it helps explain that such processes are not simply psychological or just "in the patient's head"), and I think it's important that we look for these effects in withdrawal cases routinely. I see that you've done a lot of work with FND, so if you have any ideas about how to integrate evaluating for such into withdrawal workup and management, please feel free to DM me!
I find it rather astonishing that, under an article carefully explaining the biological plausibility of protracted withdrawal, we get yet another suggestion that the underlying pharmacological disturbance has probably resolved and a functional process has taken over.
Where is the evidence for this transition, and how can we distinguish it from an unresolved physiological disturbance?
I think the paper you call seminal illustrates exactly what concerns me. It moves from the observation that we cannot consistently identify physiological causes for MUS to proposing erroneous perceptual inference as an explanation. That is a legitimate hypothesis, but what evidence supports it over physiological dysfunction we simply have not identified yet? And even if such mechanisms play a role, how much do they actually explain? All of the symptoms? Half? Ten percent? Without knowing their contribution, how can we tell whether we have explained the condition or merely identified one contributing factor?
Unexplained symptoms are an expected part of incomplete medical knowledge, not evidence for any particular explanation. Medical history is full of confident explanations for poorly understood conditions. Imagine how sophisticated our psychological models of stomach ulcers might have become had we continued refining them instead of discovering H. pylori.
Predictive processing itself is not the issue. But its application to MUS often seems to carry the authority of a tested explanation without having passed those tests.
This is not just an academic concern. Such explanations risk making us think we already understand a condition, discouraging further research into its biological causes. And down the line, they can become yet another version of "it's all in your head" with real consequences for patients.
Rather ironically, this recent review (Rethinking Predictive Processing, https://doi.org/10.1146/annurev-neuro-102124-031410) finds "inconsistent empirical evidence" for predictive processing. Apparently, inconsistent physiological evidence calls for an alternative explanation, while inconsistent evidence for that alternative calls for further refinement of the model.
How do people differentiate return of natural symptoms and delayed withdrawal? I believe many are like me and still have anxiety and depression even while on an ssri, so would that be a sign that return of symptoms on discontinuation is a reflection of an underlying default state? Maybe as well as withdrawal. I’ve tried to come off ssris a few times over the years and always had to go back on. Two of the times it all seemed like it was going well until the 6 month mark. I feel like 6 months was a time when something changed. Thanks for the article, the technicalities are over my head but I get the gist and do believe withdrawal syndromes must be possible. Sorry to hear about your journey w mirtazapine, hope you’re ok.
I do not think emergence of depression and anxiety worsening during a taper necessarily indicates relapse; that is a common misguided assumption, but part of what I tried to illustrate here is that serotonin dysregulation during tapering can produce dysregulated anxiety and mood without that representing relapse. And thank you for the condolences; I'm doing OK!
Brilliant, vital. Two thoughts: first, thank you for the gentle blade insertion re: how one should look broadly at institutions when considering the dearth of research on w/d. Second, you mention winnowing to people at high-risk people prior to w/d studies to enrich the sample and decrease the noise. Tricky, that, no? But I think there might be such a group, just based on clinical experience, viz people living with bipolarity, especially those already in a mixed state on an antidepressant. It seemed to me that nearly everyone in that group was highly vulnerable to withdrawal -- versus my primary care colleagues' experience, where so few had major problems that the PCPs didn't even routinely prescribe the lowest available dose (Phelps et al, 2025).
Thank you for your work, and this essay, and sorry to hear about what you've had to go through to learn about all this so directly. JP
Awesome! Instead of the 'Minimum Effective Concentration" (MEC) paradigm, which is appropriate for antibiotics, thinking of dynamical systems as the underlying abstractions enable new posology strategies.
You should check out these papers:
https://www.scielo.br/j/trends/a/m6MnWZ7MgTSR5Pmfq3KfnyR/?lang=en
https://www.octopus.ac/publications/w9pm-0h38/versions/latest
https://osf.io/preprints/psyarxiv/84ndb_v1
Thanks, and thanks for posting these! These are very interesting, and further illustrate how much psychiatry could benefit from application of dynamical systems concepts. I’d be curious how much some of these concepts you mention could be applied at a lower level e.g. the serotonin system itself
You are welcome! The last paper cites some studies that report natural cycles for 5HT, DA, and NE receptors, which suggests that treatment effects may vary with an oscilating posology. Nice to revisit this manuscript almost 10 years later. We also designed an RCT to test this hypothesis, but I could not get funding at the time.
- Koulu, M., Saavedra, J. M., Potter, W. Z., & Linnoila, M. (1986). Circadian covariation of norepinephrine and serotonin in the locus coeruleus and dorsal raphe nucleus in the rat. Brain Research, 397, 353–358.
- Praschak-Rieder, N., Willeit, M., Wilson, A. A., Houle, S., & Meyer, J. H. (2008). Seasonal variation in human brain serotonin transporter binding. Archives of General Psychiatry, 65, 1072–1078.
- Matheson, G. J., Schain, M., Almeida, R., Lundberg, J., Cselényi, Z., Borg, J., Varrone, A., Farde, L., & Cervenka, S. (2015). Diurnal and seasonal variation of the brain serotonin system in healthy male subjects. NeuroImage, 112, 225–231.
- Gannon, R. L., & Millan, M. J. (2007). Evaluation of serotonin, noradrenaline and dopamine reuptake inhibitors on light-induced phase advances in hamster circadian activity rhythms. Psychopharmacology, 195, 325–332.
- Carlsson, A., Svennerholm, L., & Winblad, B. (1980). Seasonal and circadian monoamine variations in human brains examined post mortem. Acta Psychiatrica Scandinavica, 61, 75–85.
- Ferris, M. J., España, R. A., Locke, J. L., Konstantopoulos, J. K., Rose, J. H., Chen, R., & Jones, S. R. (2014). Dopamine transporters govern diurnal variation in extracellular dopamine tone. Proceedings of the National Academy of Sciences, 111, E2751–E2759.
Brilliantly written. I have had some of the same hypothesis regarding delayed onset withdrawal.
I, myself have experienced 7 failed tapers with my last reinstatement being completely unsuccessful. This was puzzling to me and has led me down a path of several years worth of research.
Interestingly enough, my mother and I also developed hyperkinesis and severe bile reflux from withdrawal which has been protracted for over a decade. So sorry to hear you are going through this as well. This has been utterly debilitating, but after 22 years trying to get off SSRIs, it’s profoundly satisfying seeing all of this being talked about.
Thank you! And I’m sorry to hear you and your mother have gone through this— that is interesting that you have both experienced this related to withdrawal. Feel free to DM me if you’d like to discuss further
This is one of the more careful mechanistic arguments I've seen. You never treat variables as some isolated part doing its work on its own, such that the patient is rendered an automaton. That is my primary critique against this field. And I I commend you on invoking hysteresis, that is, time-lagged variables. If I'd push on anything, it's where the agency ends up once you use biology language. You keep narrating the serotonergic system itself as THE THING that adapts — somewhat disconnected from the whole person whose sleep/stress/serotonin dynamics you yourself point to as relevant. The "landscape" you're describing isn't really the serotonin system's landscape on its own, it's shaped by a person's WHOLE embodied and environmental situation, which you gesture at without really folding it into systems theory. If anything that makes the mechanistic case stronger. But again, I will forever attack any atomist who reduces causes to anything "smaller" than a legal person. Give me caus-ers of causes, of give me nothing.
Thank you for this great and thoughtful read! I’m both a patient with depression and a pediatric NP who Rx’s these meds (and, after personal experience brought me greater knowledge more thoughtfully deprescribes these meds as well!
On Prozac 20mg for 4 years in my early 20’s… no issues stopping. On it again for 10 years and expected no issues tapering in my late 50’s and had an AWFUL time… ultimately it took over 2 years to get off this med the 2nd time… which was most unexpected, so, I chafe at the suggestions that much of withdrawal is a patient anticipating a difficult experience.
When it happened to me, I googled. And found the info that, even as an NP, I sadly did not know. I bought Maudsley. I bought 2 copies and gifted one to my own psych NP who also did not know. I’m fortunate that he believed and supported me, because I know this is sadly not true for all patients.
I now present on this… 2nd national conference coming up next month.
Like you, I share a bit of my own experience at the end, even though that feels vulnerable… because I do think those of us in the medical field who do so adds a bit of depth to it. So, thank you for sharing your own experience!
Thank you for the kind words. I’m glad you found this helpful, and I’m sorry you’ve had to learn about withdrawal the same way I have, ie through personal experience. That is great that you present on the topic now and spread awareness! If you have any links to your talks I’d love to check them out!
I’ll be speaking at APNA in Phoenix end of October. I also have a podcast episode written and accepted for a primary care peds podcast but do not yet know when it will record/release. I have two other conference abstracts out there I’m waiting to hear on.
This is a link to my talk at NAPNAP in Pittsburgh last March… it’s recorded but not free and a bit more to access it as they bundled it with a couple other talks.
https://ce.napnap.org/content/when-healing-means-letting-go-perspective-deprescribing-antidepressants#group-tabs-node-course-default4
And… first time I spoke about this which is super vulnerable as first half is talking about how I ended up on antidepressants and last half is talking about tapering
https://podcasts.apple.com/us/podcast/back-from-the-abyss-psychiatry-in-stories/id1469826718?i=1000704890124
Hello!
This is interesting but also quite terrifying. I was thinking of tapering from Venlafaxine, and this article might have given me enough anxiety that I probably still need Venlafaxine
That was not my intention! I don't think you should be scared away from tapering, and what I was trying to establish is that careful tapering, if indicated, can make the process much safer and more tolerable.
I understand. It's just, I'd been taking various antidepressants for 10 years, and Venlafaxine specifically for 1 year, and it's eerie to think about what it had done to my brain over that time.