Having practiced psychiatry for over twenty years, I can attest to the reality of withdrawal from antidepressants, known euphemistically as ‘discontinuation syndrome’, as if relabeling the phenomenon diminished the psychological and physical pain associated with abrupt stoppage or aggressive tapering.
Thank you for the no nonsense clarity in this post, Dr. Ward. You speak up for many who are often denied their own voice. Very slowly does the tide turn. It was in 2022 that Professor Joanna Moncrieff published her paper and book, Chemically Imbalanced, which effectively challenge the prevailing paradigm of mental illness and existing "treatments", which she disparages unflinchingly.
Dr. Moncrieff's work is now shaping the discussion around these issues. Changes are coming, just far too slowly for anyone's liking, but of course billions of dollars of profit and investment needs to be paramount so we'll have to deal with that first, it seems.
Thank you for this marvellous contribution towards a more responsible and evidence-based approach to mental and emotional well-being. It is sorely needed.
It seems to me that the uncertainty presented here can and should be evaluated through a series of high-quality n-of-1 randomised controlled trials. Indeed, it appears such a study is currently ongoing (and results should be due any time now):
As the spouse of a person devastated by rapid weaning after several years on the same dose, I know that withdrawal is real. The thing that so many physicians and researchers seem to fail to understand is that not all human bodies respond to substances in an identical way. We need to accept and deal with the fact of variability from one person to the next. Generalizations have applicability but must not be considered absolute.
Even IF the studies included significant long term user experiences and STILL found little statistical evidence that withdrawal symptoms were the norm, there will ALWAYS be some patients who do not fall into those parameters. Doctors should always be prepared to look for those outliers. Partly, to alleviate their suffering as best as possible but also...those are the people who head to the internet and broadcast their experiences to everyone. And they will be believed over any study that might say otherwise. It is time that the medical community come to grips with what Dr Google and his associate Dr. Reddit are seeing out in the world. It is a force to be reckoned with.
"And if this is true, the authors’ meta-regression was flawed". AND, it would appear at least possible if not highly likely that these flaws were understood and yet this study made no mention of them.
It would seem near impossible to conduct a scientific study of the effects of drug withdrawal that carry a heavy psychological component when the people are receiving the drugs to ameliorate psychological problems to begin with. Sorting out the placebo/nocebo effects from those of the drug itself and then its discontinuation would seem to require a lot of speculation. Add to that a meta-analysis and the chance of coming up with anything remotely scientific is extremely unlikely.
Two additional critiques that seem important to highlight:
1) The conflict of interest statement is a mile long. It’s in the pharmaceutical industry’s interest to downplay any withdrawal syndrome, so it’s not a difficult logical leap to presume an ideological bias among the authors, especially since they so strongly advocate for this flawed meta-analysis to influence clinical guidelines. As Dr. Horowitz notes, one of the authors (Allan Young) was part of the original push to downplay this in the 90s (https://mhorowitz.substack.com/p/no-the-kalfas-meta-analysis-doesnt)
2) I don’t think it’s mentioned here or in Horowitz’s analysis that a large majority of the included studies had an incredibly short follow-up period; of the 51 studies included in eAppendix 2, 39(!!) of them studied patients for two weeks or less. Only four formally tracked patient outcomes beyond 12 weeks. Providers who see patients with withdrawal syndrome will point out that a majority of patients who experience withdrawal do so after 2 weeks, so the studies will miss a substantial number of individuals who could develop issues.
The article now has a correction linked that says " ...one of the coauthor’s disclosures was inadvertently omitted. The Disclosure section has been corrected to include: “Dr Young reported personal fees from Flow Neuroscience, Novartis, Roche, Janssen, Takeda, Noema Pharma, Compass, AstraZeneca, Boehringer Ingelheim, Eli Lilly and Co, LivaNova, Lundbeck, Sunovion, Servier, Allergan, Bionomics, Sumitomo Dainippon Pharma, Sage,......" that sure is a lot of pharma fees.. 🧐🤔
I went and read the PREVENT study and found this statement:
Discontinuation due to adverse events was more common in the group receiving placebo, which may represent adverse events related to the discontinuation of Venlafaxine ER.
The authors were not unaware that discontinuation syndrome exists for these meds, evidently.
I have had many patients tell me they will not consider any antidepressant now or in the future because it was so hard for them to come off venlafaxine. Whenever I begin a discontinuation process of an antidepressant with a patient, I give them a whole talk about discontinuation syndrome, partly because it can be so unpleasant that people just go back on the med and also sometimes peole think there's something wrong with them because they're having troubles getting off it.
This is not my area, but this is a fantastic commentary on medical research that is agnostic to the specifics of the clinical question: even when you have a patient who looks like the enrolled subjects in a clinical trial (ie meets all inclusion criteria), and the intervention/treatment in question was shown to be “beneficial”, in real world practice, how long do you keep a pt on therapy?
The reality is that ALL therapy trials are of limited duration…since you have to conclude at some point. In my field (cardiology), 3-5 years would be considered long follow up. The issue with very long (and very large) trials (beyond the logistics and cost of conducting such a study) is that it becomes easier for small treatment effects to reach statistical significance. There are results that we not infrequently ignore which are “statistically significant” (ie considered “real”) but of no clinical significance (due to very small treatment effect size). But even in cases of “real” effects that are “worth pursuing”, once a pt has been on therapy beyond the duration of the foundational study, we are in an evidence-free zone.
I see many pts on SSRIs in passing. So it is a bit disconcerting to find out that the evidence basis for their use is grounded on studies that are generally only 2-3 months in duration. In my med school days (last century), I recall terminology like “major depressive episode”. It seems like these trials were designed to test for benefit in treating such episodes, rather than as used for “chronic” conditions.
This seems like a corollary to the LAAO saga that Dr. JMM speaks of, but writ much larger. If millions of people have been given these drugs for decades, why didn’t somebody somewhere deem it necessary for purveyors to first prove (or at least concurrently prove) efficacy and safety?!?
Because of the very large profits involved, I'd say. Billions of dollars are on the table. Individuals are a secondary concern. They either continue to take the 'treatment' or they don't.
Which outcome would the companies selling the drugs prefer? That will be the route made most accessible to the aggrieved. And it will all be perfectly legal. They'll make sure of that part. That's just operating manual basics.
I just follow the money. The story is always there. It eliminates the need for questions like 'why didn't somebody' do the right thing? Ka-ching!
In my non-professional estimation, instead of trying to push SSRIs on everyone with even the slightest mental health issue (for which there is no test), doctors should be trying to find ways to keep patients off of these drugs.
Taking these drugs does NOTHING to alleviate the true cause of mental anguish or trepidation. It is NEVER a chemical imblance as they want us to believe without question. Drugs are the trap to keep you drugged forever. Does the doctor ever tell you you can get off your meds? That they will cure you so that you won't need them any longer? Very seldom.
These drugs can be used for critical interventions over short periods (a few weeks, generally). However, that is not the business model. Any Substack subscriber understands subscriptions, and that's what this is.
Profit demands unquestioning, dependent customers. Ask the guy peddling drugs at the corner somewhere in your city. That's the real.
It's not about people's well-being. It's about money. Individuals are secondary, tertiary, etc. Business runs the show. They know what you just said is true better than you do, and they don't care. They really, really don't give a flying you know what, do they? We wouldn't be having these conversations otherwise.
Imagine you wanted to create a fake drug with spurious benefit and intentionally dupe the public. Basically you would create the trials, narrative, and theater of antidepressants except call them something else. Antidepressant research is a tome of how to violate basic tenets of good science. Not even the short terms trials say what they claim they say.
Great article and I hope many read it and heed it! I can assure you I know the different kinds of withdrawal I have experienced over the years…opiates, check. Alcohol, check. Nicotine, check. Venlafaxine withdrawal was by far the most unpleasant for the longest time. I’d been on it >10 years. I am very glad I got sober - especially for the opiates - when I did prior to buperenorphine. Many “experts” in OUD stated that there is no withdrawal from it. Nearly every person I treated who was on it and wanted off had withdrawal worse than heroin. I wonder if there’s been an analysis on that?
Dr. Mandrola, I'm a frequent reader of Sensible Medicine, but I still find it fascinating that you are ready to publish articles that dispute your own writing. I know, it should be standard, but we are far away from standard recently. Disagreements are mostly published as a fierce rebuttal, with personal attacks and language that guarantees very strong language back. Or not published at all. Disagreements published here make me believe that science can still work as it's supposed to. Through politely formulated objections, questioning, and proposals for amendments. Thank you for that.
Having practiced psychiatry for over twenty years, I can attest to the reality of withdrawal from antidepressants, known euphemistically as ‘discontinuation syndrome’, as if relabeling the phenomenon diminished the psychological and physical pain associated with abrupt stoppage or aggressive tapering.
Thank you for the no nonsense clarity in this post, Dr. Ward. You speak up for many who are often denied their own voice. Very slowly does the tide turn. It was in 2022 that Professor Joanna Moncrieff published her paper and book, Chemically Imbalanced, which effectively challenge the prevailing paradigm of mental illness and existing "treatments", which she disparages unflinchingly.
Dr. Moncrieff's work is now shaping the discussion around these issues. Changes are coming, just far too slowly for anyone's liking, but of course billions of dollars of profit and investment needs to be paramount so we'll have to deal with that first, it seems.
Thank you for this marvellous contribution towards a more responsible and evidence-based approach to mental and emotional well-being. It is sorely needed.
It seems to me that the uncertainty presented here can and should be evaluated through a series of high-quality n-of-1 randomised controlled trials. Indeed, it appears such a study is currently ongoing (and results should be due any time now):
https://pmc.ncbi.nlm.nih.gov/articles/PMC10576328/
https://www.clinicaltrials.gov/study/NCT05051995?tab=results&utm_source=chatgpt.com
Thank you for this important article.
As the spouse of a person devastated by rapid weaning after several years on the same dose, I know that withdrawal is real. The thing that so many physicians and researchers seem to fail to understand is that not all human bodies respond to substances in an identical way. We need to accept and deal with the fact of variability from one person to the next. Generalizations have applicability but must not be considered absolute.
Even IF the studies included significant long term user experiences and STILL found little statistical evidence that withdrawal symptoms were the norm, there will ALWAYS be some patients who do not fall into those parameters. Doctors should always be prepared to look for those outliers. Partly, to alleviate their suffering as best as possible but also...those are the people who head to the internet and broadcast their experiences to everyone. And they will be believed over any study that might say otherwise. It is time that the medical community come to grips with what Dr Google and his associate Dr. Reddit are seeing out in the world. It is a force to be reckoned with.
Bravo thank you for pointing out why so many have a very difficult time coming off these drugs. Most folks have been on these drugs for decades
"And if this is true, the authors’ meta-regression was flawed". AND, it would appear at least possible if not highly likely that these flaws were understood and yet this study made no mention of them.
SHAMEFUL. This is where we are at.
It would seem near impossible to conduct a scientific study of the effects of drug withdrawal that carry a heavy psychological component when the people are receiving the drugs to ameliorate psychological problems to begin with. Sorting out the placebo/nocebo effects from those of the drug itself and then its discontinuation would seem to require a lot of speculation. Add to that a meta-analysis and the chance of coming up with anything remotely scientific is extremely unlikely.
Two additional critiques that seem important to highlight:
1) The conflict of interest statement is a mile long. It’s in the pharmaceutical industry’s interest to downplay any withdrawal syndrome, so it’s not a difficult logical leap to presume an ideological bias among the authors, especially since they so strongly advocate for this flawed meta-analysis to influence clinical guidelines. As Dr. Horowitz notes, one of the authors (Allan Young) was part of the original push to downplay this in the 90s (https://mhorowitz.substack.com/p/no-the-kalfas-meta-analysis-doesnt)
2) I don’t think it’s mentioned here or in Horowitz’s analysis that a large majority of the included studies had an incredibly short follow-up period; of the 51 studies included in eAppendix 2, 39(!!) of them studied patients for two weeks or less. Only four formally tracked patient outcomes beyond 12 weeks. Providers who see patients with withdrawal syndrome will point out that a majority of patients who experience withdrawal do so after 2 weeks, so the studies will miss a substantial number of individuals who could develop issues.
The article now has a correction linked that says " ...one of the coauthor’s disclosures was inadvertently omitted. The Disclosure section has been corrected to include: “Dr Young reported personal fees from Flow Neuroscience, Novartis, Roche, Janssen, Takeda, Noema Pharma, Compass, AstraZeneca, Boehringer Ingelheim, Eli Lilly and Co, LivaNova, Lundbeck, Sunovion, Servier, Allergan, Bionomics, Sumitomo Dainippon Pharma, Sage,......" that sure is a lot of pharma fees.. 🧐🤔
prostitutes see fewer clients
That's funny
I went and read the PREVENT study and found this statement:
Discontinuation due to adverse events was more common in the group receiving placebo, which may represent adverse events related to the discontinuation of Venlafaxine ER.
The authors were not unaware that discontinuation syndrome exists for these meds, evidently.
I have had many patients tell me they will not consider any antidepressant now or in the future because it was so hard for them to come off venlafaxine. Whenever I begin a discontinuation process of an antidepressant with a patient, I give them a whole talk about discontinuation syndrome, partly because it can be so unpleasant that people just go back on the med and also sometimes peole think there's something wrong with them because they're having troubles getting off it.
My mom was one. She was so angry
This is not my area, but this is a fantastic commentary on medical research that is agnostic to the specifics of the clinical question: even when you have a patient who looks like the enrolled subjects in a clinical trial (ie meets all inclusion criteria), and the intervention/treatment in question was shown to be “beneficial”, in real world practice, how long do you keep a pt on therapy?
The reality is that ALL therapy trials are of limited duration…since you have to conclude at some point. In my field (cardiology), 3-5 years would be considered long follow up. The issue with very long (and very large) trials (beyond the logistics and cost of conducting such a study) is that it becomes easier for small treatment effects to reach statistical significance. There are results that we not infrequently ignore which are “statistically significant” (ie considered “real”) but of no clinical significance (due to very small treatment effect size). But even in cases of “real” effects that are “worth pursuing”, once a pt has been on therapy beyond the duration of the foundational study, we are in an evidence-free zone.
I see many pts on SSRIs in passing. So it is a bit disconcerting to find out that the evidence basis for their use is grounded on studies that are generally only 2-3 months in duration. In my med school days (last century), I recall terminology like “major depressive episode”. It seems like these trials were designed to test for benefit in treating such episodes, rather than as used for “chronic” conditions.
This seems like a corollary to the LAAO saga that Dr. JMM speaks of, but writ much larger. If millions of people have been given these drugs for decades, why didn’t somebody somewhere deem it necessary for purveyors to first prove (or at least concurrently prove) efficacy and safety?!?
Because of the very large profits involved, I'd say. Billions of dollars are on the table. Individuals are a secondary concern. They either continue to take the 'treatment' or they don't.
Which outcome would the companies selling the drugs prefer? That will be the route made most accessible to the aggrieved. And it will all be perfectly legal. They'll make sure of that part. That's just operating manual basics.
I just follow the money. The story is always there. It eliminates the need for questions like 'why didn't somebody' do the right thing? Ka-ching!
In my non-professional estimation, instead of trying to push SSRIs on everyone with even the slightest mental health issue (for which there is no test), doctors should be trying to find ways to keep patients off of these drugs.
Taking these drugs does NOTHING to alleviate the true cause of mental anguish or trepidation. It is NEVER a chemical imblance as they want us to believe without question. Drugs are the trap to keep you drugged forever. Does the doctor ever tell you you can get off your meds? That they will cure you so that you won't need them any longer? Very seldom.
These drugs can be used for critical interventions over short periods (a few weeks, generally). However, that is not the business model. Any Substack subscriber understands subscriptions, and that's what this is.
Profit demands unquestioning, dependent customers. Ask the guy peddling drugs at the corner somewhere in your city. That's the real.
It's not about people's well-being. It's about money. Individuals are secondary, tertiary, etc. Business runs the show. They know what you just said is true better than you do, and they don't care. They really, really don't give a flying you know what, do they? We wouldn't be having these conversations otherwise.
Imagine you wanted to create a fake drug with spurious benefit and intentionally dupe the public. Basically you would create the trials, narrative, and theater of antidepressants except call them something else. Antidepressant research is a tome of how to violate basic tenets of good science. Not even the short terms trials say what they claim they say.
Great article and I hope many read it and heed it! I can assure you I know the different kinds of withdrawal I have experienced over the years…opiates, check. Alcohol, check. Nicotine, check. Venlafaxine withdrawal was by far the most unpleasant for the longest time. I’d been on it >10 years. I am very glad I got sober - especially for the opiates - when I did prior to buperenorphine. Many “experts” in OUD stated that there is no withdrawal from it. Nearly every person I treated who was on it and wanted off had withdrawal worse than heroin. I wonder if there’s been an analysis on that?
Dr. Mandrola, I'm a frequent reader of Sensible Medicine, but I still find it fascinating that you are ready to publish articles that dispute your own writing. I know, it should be standard, but we are far away from standard recently. Disagreements are mostly published as a fierce rebuttal, with personal attacks and language that guarantees very strong language back. Or not published at all. Disagreements published here make me believe that science can still work as it's supposed to. Through politely formulated objections, questioning, and proposals for amendments. Thank you for that.