Evidence of a nocebo response following a nationwide antidepressant drug switch
cpe.psychopen.eu
cpe.psychopen.eu
“While only half of these trials had formally significant effectiveness, published reports almost ubiquitously claimed significant results. "Negative" trials were either left unpublished or were distorted to present "positive" results.”
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2412901/
If this is true, then many people who currently take antidepressants may actually be better, not worse, without them, since at least they’d avoid the side effects.
Further, the “chemical imbalance” theory that is propagated through paid advertising has no applicability to a doctor prescribing an antidepressant, since the doctor has no way of measuring and monitoring that imbalance should one exist.
I've never seen a pharmaceutical ad that used that term. The only thing I recall from the ads is them distinguishing clinical depression from feeling blue.
Example, probably the most the most recognizable anti-depressant ad ever (at least in the US): https://m.youtube.com/watch?v=twhvtzd6gXA @ 0:20
Funny thing about psychosis — when you’re psychotic, your erratic and extreme behavior doesn’t feel abnormal. You don’t feel like anything has changed. This happened to me on Prozac — the most commonly prescribed antidepressant — and it took me 3 years to put my life back together after all the damage I did to my personal relationships during that period.
The anxiety I was dealing with was crippling, but it didn’t dismantle my life the way the side effects of that drug did. The treatment was absolutely worse than the disease. If they had done a genetic test first, they would have seen a red flag and avoided SSRIs all together.
This testing exists today, but it’s only used in patients who show strong resistance to pharmacological intervention. It should be standard.
TED talk by Jack Gallant https://www.youtube.com/watch?v=Ecvv-EvOj8M
recreating vision: https://www.youtube.com/watch?v=nsjDnYxJ0bo
another ted talk by John-Dylan Haynes https://www.youtube.com/watch?v=mMDuakmEEV4
paraphrased: "wireless non-contact mind reading tech may be cheap and mass producible within the next 50 years."
the only rate limiting step with his method of decoding thoughts is that it takes time under a high energy device to pair associations in the brain.
Think of how much screen time we currently use. If we could pair a wireless 'headset' like headphones while looking at pictures on a screen it would be possible to build a brain bank of children->tenenagers. Currently we just need a lot of processing power and reserved bandwidth on the internet to do some cool stuff.
1. Our understanding of the brain is poor, and I think that will be necessary to have good machine decoding. In principal, a machine learning algorithm does not need to know how the brain works to make an accurate decoding prediction, but I suspect understanding will be needed to help construct and constrain machine learning models learn to deal with the myriad of mental states, intentions, emotions, etc that can occur. While we can train classifiers better than chance to identify whether one or another item is observed, remembered, etc, these training are quite constrained to a type of information or class. I imagine those classifiers are hopeless when you start performing another activity or mental state, and the machine would need to recognize the new state and apply different decoders.
Second, yes there is too much noise in most available methods (EG, fMRI, MEG) and the information is not dense enough (spatial, temporal resolution) and not specific enough to the type of activity (excitation, inhibition, chemical diffusion, etc). Electrodes have done cool things, but I suspect that even millions of wires would not provide enough information and types of information to provide a full fledged brain interface.
However, I'll admit, tech is moving so fast...
So many cancer treatments go into clinical trials with only the evidence that it shrinks tumors, and tends to kill tumors faster than it kills the rest of your body. Side effects are expected to be severe since most cancer treatments are quite literally killing any cells that divide... tumors just divide faster and thus get hit harder. The end result is cancer treatment often has very poor quality of life.
Clinical researchers _do_ perform analysis to see if survival increases relative to other treatments. But often you don't know until you've already tried it on a cohort of patients (with their consent, obviously).
There is push-back in the medical field in areas for what you suggest. For example, colonoscopies are becoming widely recognized as causing more problems than they solve. The complications they can induce tend to lead to a poorer patient outcome than missing colon cancer because you didn't screen (e.g. survivability is not affected by finding/treating colon cancer early).
I just don't think it's fair to paint cancer treatments with the same brush strokes, since dealing with terminal diseases is a totally different ball game.
Edit: I should say, there are some parts of cancer treatment which is moving towards the dont-treat opton. For example, there is growing evidence that treating prostate cancer is not necessary, since you'll probably die of something else long before prostate cancer kills you (it is very slow growing on average)
Is it possible to do this kind of thing oneself with 23andme style SNP tests and a google scholar search, or does it involve more than that?
https://slatestarcodex.com/2019/05/07/5-httlpr-a-pointed-rev...
As far as negative results being "distorted" to present "positive results" is concerned, yes it is quite common to take a patient population that overall fails to show statistically significant benefit and see if there is a subset that does in fact show a statistically significant benefit. One could call that p-hunting, but as long as it is followed up and confirmed, it doesn't seem like a nefarious thing to do.
He just wants a silver bullet.
And yes, most psychiatrists don't want the liability of weaning somebody off a medication.
You are right, it doesn't make any sense--it certainly is not good for patients.
But believe me there are bad doctors out there (your specific case) so you'll have to switch.
The problem is not with individual doctors, it is that the structure {legal, economic} surrounding mental health favors getting people on medication, but doesn't create good paths for them to get off (at least in the US).
I’m sure there will be/are places where these databases are run by private companies with no accountability and no way to issue a complaint.
When I was in my 20's I tried various SSRIs - at least three, possibly four different ones - and my pattern was always the same, which was to take them for six months, get frustrated because they didn't do anything but make my hands shake, etc., then flush them down the toilet and quit cold turkey with no ill effects. Same thing with Ritalin. I was taking it for a few years because it (shockingly!) made me a more prolific computer programmer, then my doctor moved to California and I never got a new prescription. No withdrawal whatsoever that I noticed.
My personal, subjective, anecdote-based take on this is the stories of withdrawal are as overblown as the stories of effectiveness for a lot of these.
Some drugs are relatively benign to quit cold turkey (a sizable percentage of people may run into irritating side effects like nausea, etc) but it won't kill you.
Other drugs like benzos can be fatal to quit without tapering. And other classes can induce serious side effects even when properly tapering, let alone quitting cold-turkey (e.g. hallucinations, psychosis, insomnia, etc etc).
Just look up the video where Feynman is describing how two different people count to 100 in two completely different ways.
A few days later, I came back from taking the trash out to find her on the floor, gray and wheezing and totally unresponsive, having suffered from a serious seizure due to medication withdrawal. On waking up, she had serious amnesia (couldn’t remember the year, who the president was, etc.) for a couple of hours.
Please don’t assume that anecdote == data, or that your personal experience with one medication is generalizable to other people and other medications.
Those several weeks were hell. I was having anxiety attacks all the time.
I initially thought something else was wrong and didn’t even consider withdrawal (since the doctor had said I should have no issues) but later googling revealed withdrawal was pretty common with the drug I was on.
I’m just glad it’s over.
https://www.nytimes.com/2019/03/05/health/depression-withdra...
"In a paper published Tuesday in Lancet Psychiatry, the authors argued that any responsible withdrawal regimen should have the patient tapering off medication over months or even years, depending on the individual, and not over four weeks, the boilerplate advice."
That’s the problem with all this experimentation.
We had 4 decades for doctors to get interested in them, study them, and make protocols for them for the public.
Only now are we, timidly, talking about them. It was considered hippie stuff at best, cult/lunatic ideas at worst.
But turning an entire nation into drug addict is apparently fine.
What they want is the doctor to provide a pill to fix whatever the immediate issue is, so they can get back to their life. When providers push back on this and try to suggest lifestyle changes, many patients get _angry_. Like, yelling, shouting, complaining to administrators that the provider isn't "listening to them" or "not taking their problems seriously". People want to be fixed, not fix themselves.
There's plenty of blame to go around, but a healthy share falls on patients themselves.
Source: SO is a medical provider. My faith in humanity falls daily and I can't believe the crap providers have to put up with. It's like a service job dealing with irritated people all day long, except these people read a blurb on WebMD and think they are an expert.
Yes, but it's also very hard to do. I took me 30 years to actually have a nervous and hormonal system that was not fucked up.
Before that, I tried for decades to restrain myself and exercise, and it was just not sustainable. I had to read so much, go through so many experiments, meet and talk to so many people to find all the stuff I needed to actually fix myself. And the work is far from over, I have yet a lot to do.
I was kind of expecting medical professionals to pick up on what I needed, and actually helped me on the way. 2 did a little, out of probably 30. And I met them only because my close ones were atypical, and know original people.
Our health culture is failing big time here.
Stream-of-consciousness about these (sorry a bit off topic):
1) Detach yourself from "culture" and try to meditate, do breathwork, some people get into this zone better while doing stuff like Tai Chi, Yoga or Chi Gong. Go slower!
2) Exercise but find something that your body responds well to and don't over do it (many people exercise mindlessly)
3) Be social, you are a mammal and need to be touched and feel other peoples breath, warmth and voice close to you - it's a part of tribal nature, and balances your sympathetic nervous system
4) Get out in the sun and stroll around without purpose sometimes just walking, thinking, exploring the city/forest - again we are wanderers in our genetic heretage (you often think better when walking without purpose - french people call it Flâneur)
5) Create more than you consume: write, work, plan, set goals. Without a plan you are walking aimlessly and will run out of resources, feel left out and wither.
6) Eat and drink well. (fast sometimes, less junk food, more vegetables, enough protein for activity level, more organ meats if meats at all)
7) Be brutally honest towards yourself, but acknowledge that self image is malleable and mysterious like the rest of the universe. So always have an echo of awe in the back of your mind. This reality is amazingly absurdly weird, wonderful, mysterious, dreamlike, filled with obscure esoteric symbols of knowledge and history and tradition and truth in an all encompassing and infinite web all around you and your consciousness.
8) Read challenging fiction, do math, play and instrument. (or some one of these, it has to be difficult)
Understand this key is a chain where all parts are equally important like:
Learn to imagine so you can make a plan or have a vision. Imagination is a precursor to planning, and meditation and unplugging is a precursor to to this imagination. If your mind is clouded the first plan is to eat well, rest, and slowly introduce exercise until your mind is in a state of clarity, and you can actually feel "something" in your gut (ie intuition or your second brain), then you feel what you "want" in you gut, and create your plan with your non-clouded mind.
- my testosteron was low, and that I was missing omega 3, d vitamin and magnesium.
- my digestive system was in crisis.
And fix that.
Without it, you can't find the energy and motivation to do the rest all year round.
After a while, they help each other.
The next step is to cut out on sugar.
They based their initial "he's ok" on a single temperature check after I'd taken Panadol. I get it, when a doctor hears hooves they think horses. It's just frustrating.
I'd rather have the option of anti-depressants than nothing at all. They help a lot of people to live their life normally. It's true that it's hard coming off some of them, but it's worth it I think - a couple years of improvement in mental health vs a crappy week coming off it.
Please tell us about the alternative treatment regimen you recommend, with references to the peer-reviewed, published literature supporting its efficacy.
I like the idea of measuring. How would we do it though?
This is still true after seeing the results of well-done scientific experiments. They can tell you the average effect and how much it varies, but not the effect on you personally.
We really only have one amazing piece of technology at our disposal: statistics. At the absolute best (and I'm not saying it's always the best...), what comes out of a pharmaceutical development pipeline is a drug that works for some people some of the time. Sure, sometimes you get broad categories to try to narrow down effectiveness, but at the individual level there is ultimately no choice but to try a drug and see if it works. And this is especially true in psych drugs, in no small part because there are so many unanswered questions about how our mind works.
And that sucks. I get it. It must be so frustrating to deal with a revolving door of new regimens and new side effects, all while yearning for relief from the underlying ailment. Not to mention navigating our nightmarish medical bureaucracy. But please understand that doctors, generally, are just doing their best to help given the tools they have. If you don't currently have that kind of trust and partnership with your doctor, I hope you are able to find one with which you can. I wish you the best, and hope that this perspective will make your frustrations somewhat easier to bear.
But we don't know, despite enormous and ongoing effort. Hopefully we'll understand eventually, but right now we don't. I'm sorry if that fact is upsetting, but you can't will knowledge into existence.
Ben Goldacre, a UK physician and medical researcher, captures it really well in the opening two paragraphs of his book 'Bad Pharma':
> Drugs are tested by the people who manufacture them, in poorly designed trials, on hopelessly small numbers of weird, unrepresentative patients, and analysed using techniques which are flawed by design, in such a way that they exaggerate the benefits of treatments. Unsurprisingly, these trials tend to produce results that favour the manufacturer. When trials throw up results that companies don't like, they are perfectly entitled to hide them from doctors and patients, so we only ever see a distorted picture of any drug's true effects. Regulators see most of the trial data, but only from early on in a drug's life, and even then they don't give this data to doctors or patients, or even to other parts of government. This distorted evidence is then communicated and applied in a distorted fashion.
> In their forty years of practice after leaving medical school, doctors hear about what works through ad hoc oral traditions, from sales reps, colleagues or journals. But those colleagues can be in the pay of drug companies – often undisclosed – and the journals are too. And so are the patient groups. And finally, academic papers, which everyone thinks of as objective, are often covertly planned and written by people who work directly for the companies, without disclosure. Sometimes whole academic journals are even owned outright by one drug company. Aside from all this, for several of the most important and enduring problems in medicine, we have no idea what the best treatment is, because it's not in anyone's financial interest to conduct any trials at all.
His book, which lobbed a grenade into the heart of the pseudo-scientific state of 'modern medicine', has resulted in more energy being put into trying to move to science-based medicine with things like https://opentrials.net/, but I don't closely observe that industry, so perhaps someone else within the sector could speak to how far the idea of publicly available trial data has gone in 2019.
But yes, there are plenty of inadequacies in our healthcare industry (speaking from the US), but that's a much, much broader discussion.
Statistics can point you into a direction, however it won't account for nuances in most or perhaps all cases.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3736946/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4592645/
Or doesn't work. We don't accept this in other areas why medicine? Modern medicine in a lot of cases is as modern as when the doctor went to school and stops evolving once school finishes.
There is a disconnect between research and medical knowledge by frontline workers.
I just wanted to point out that while I can empathize with this sentiment, in the United States at least, physicians must undergo yearly retrainings to earn continuing education credits (for medicine) and there is a certain number of credits that must be acquired on a yearly basis.
There's an initiative called MEZIS (Mein Essen zahle ich selbst - "I pay for my lunch myself") that wants to end this practice. https://mezis.de/
Why do many, many doctors say there is? It seems they, of all people, should know what they are talking about.
Also, general physicians have to be across such a vast range of ailments and treatment options, they don't have much ability to deeply understand the issues themselves.
I'm not one for any great conspiracy behind this.
For my own reasons I've researched the topic deeply, and I agree that the term "chemical imbalance" is fairly shaky, but I can accept a fairly innocent explanation for why it's come to be.
This seems like a rather novel point of view. I can’t speak to whether this view is common among medical practitioners, but as a patient I can say I dislike it.
I would like that treatment options be selected and evaluated on the basis of empirical evidence.
What does it even mean that medicine is an art?
How do you balanced the subjective benefits against the potential risks and decide if (continuing) treatment is worth it? That would seem to be something without a "right" answer.
The drugs used to treat autoimmune diseases are “tested” by patients much the same way as antidepressants. Though there’s at least some bloodwork to guide the way. I’m optimistic technology and our rapidly growing understanding of gut bacteria will greatly improve the current trial and error approach.
[1] https://www.sciencealert.com/antidepressant-chemicals-are-ch...
“There is no scientific basis to do that.”
That’s a political statement. You are trying to disqualify clinical experience and an empirical approach, despite both being part of the Western scientific method for several centuries. Your view is popular and is gaining momentum everyday. Your view suggests that only double blind studies and statistical analysis amounts to “real science”. Your view has powerful factions in business that are supportive. Your view is going to do tremendous damage. Your view is ahistorical. I can only hope that you will reevaluate your view, and realize how much richer and broader the Western scientific tradition is.
Being treated by any doctor (other than a surgeon when on the verge of death) has only over the past century become something that was likely to extend your life rather than shorten it. This is a result of double-blind studies and statistical analysis.
"This is a result of double-blind studies and statistical analysis."
First of all, if you want to shrink all of medical research to seeing a doctor, do you have any evidence that your statement is true?
Second of all, most of the big breakthroughs in life extension were thanks to medical research that was neither double blind nor statistical, including:
1.) In the late 1700s, Edward Jennings invents the vaccine for smallpox.
2.) John Snow's theory of cholera in London 1854
3.) In the late 1800s Louis Pasteur and Joseph Lister develop the Germ Theory Of Illness, including such practical ideas as:
3.a) Louis Pasteur invents pasteurization.
3.b) Lister uses antiseptics to sterilize surgical instruments and clean wounds
4.) Alexander Fleming invents penicillin
1. The whole 'chemical imbalance' thing is a gross over-simplification that might help as an introductory mental model but breaks down quickly.
2. The right thing to be measuring is symptoms, not the mythical chemical imbalance. Studies do measure changes in symptoms, typically using various rating scales, e.g. HAM-D. Measuring this way has its issues and challenges, but is being done.
3. Yes, there is an element of experimentation to find the right medication, which is hardly unique to psychiatric medications.
4. Yes, some medications are hard to quit without doing so slowly. Too many doctors don't help their patients with this.
5. Antidepressants are surprisingly effective, at least compared with many other medications. A good metric for effectiveness is the "number needed to treat" (NNT). It basically means how many people do you have to give a treatment to before you get a positive response that you otherwise wouldn't. With antidepressants, it's generally low single digits, for many around 4. Only helping 1 in 4 doesn't sound great. But check out theNNT.com for some comparisons. Aspirin to prevent heart attacks (NNT of 50-200 for people with previous heart disease, NNT 2000+ for those without previous heart disease). Antihypertensives (NNT ~100). See what's considered successful in other areas of medicine...
The NNT for antihypertensives to lower blood pressure is essentially 1, after all.
I wonder how many patients had their complaints written off for the six years the generic was on the market?
For instance, I'm an asthmatic and I need to use a spray inhaler. The no-brand equivalent is exactly the same, and does work the same in normal circumstances, except has roughly 1/2 of the propellant. But I can tell you that the missing propellant makes all the difference when you're having a stronger attack and cannot inhale.
Or who didn't even bother reporting their complaints in the first place.
She will no doubt be part of the statistics that paper is using to suggest a nocebo effect, as she only complained publicly after the media coverage started, but she has notes showing she had noticed the effect prior to seeing anyone else complain about the generic formulation.
To be clear: her experience is absolutely not proof that Enlafax is in any way inferior or different than Effexor (for my partner specifically, or for people in general)! It's very possible her entire experience was a nocebo effect (triggered, perhaps, by the Enlafax packaging or something) followed by a placebo effect when she switched back to the branded drug. However, it could equally have been caused by Enlafax being actively inferior for her.
What I think is fairly clear from my partners experience, however, is that the study is not correctly designed to reject the null hypothesis here. It's assuming that the people who publicly complained about Effexor after the media coverage were fine with it until the media coverage, whereas it's just as plausible that they simply didn't publicly complain until they realised other people were also having an issue.
Ultimately, any study here that's not a proper double blind test is going to struggle pretty hard here, and I think this is no exception.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4172306/
Just goes to show how powerful the media is at shaping/controlling the individuals reality.
"These switches to generic medical and psychotropic medications have from time to time caused an increase in reported adverse events, and this is likely to be due to negative attitudes towards generic medicines rather than pharmacological differences between the branded and generic versions of the medication.
This phenomenon is known as the nocebo effect"
NZ has socialized medicine, with a central drug buying agency (Pharmac) who tries to save costs where it can. It also has a drug safety agency (Medsafe). Not uncommonly, Pharmac reckons they can save money by switching brands, and Medsafe may raise concerns.
In 2017, Pharmac moved from funding a branded formulation of venlafaxine (Effexor) to a generic formulation (Enlafax). A lot of patients reported issues (almost 2k, which is a fair number given the size of the country), and it was a bit of a black eye for Pharmac. So Pharmac went and paid a researcher at a local university to study brand switches in general and the 2017 venlafaxine switch in particular, and show (hopefully) that the issues weren't real, hadn't caused significant problems, and that it was totally fine to switch psychiatric meds. (Which is relevant now, because Pharmac is looking at switching another medicine, Medsafe has raised strong concerns ("potential significant safety issues", "goes against international consensus", etc.), and Pharmac wants to find a way to move forward while covering their ass in case it turns out Medsafe is right.)
In any case, the result was this study. It could well be right, but uh, do keep in mind the context, which is that the researchers got paid hundreds of thousands of dollars to conduct it by an interested party hoping to save millions of dollars and fend off accusations that they had harmed people and risked lives.
Any study funded by people with such a strong interest in it having a specific outcome that then comes out with the exact outcome should be taken with a grain of salt. Doubly so when the study omits to disclose that funding!
Local NZ article with a good roundup of the current controversy, the 2017 issues, and the linked study: https://www.rnz.co.nz/news/in-depth/390615/guyon-espiner-inv...
Note: The article says that Petrie received NZ$400k from Pharmac for the study. For anyone wondering if that's right, the answer is: Yes! Although it took the NZ equivalent of a FoI request to find out. See https://www.pharmac.govt.nz/news/oia-response-2018-12-12-res... And note that the study itself disclosed nothing about funding. Given that Pharmac has a very strong and very obvious vested interest in this matter, I find this ethically troubling.
Crap study, just an excuse for a publication.
Knowing these side effects are associated with the intervention would likely be enough for Confirmation Bias to increase the reported instance.
while talking extensively about the nocebo effect, it ignores the fact that without media coverage a patient may experience side effects but not connect that effect with the switch from one drug to another, or may think they're imagining the effect, etc
wa? the power of branding -- advertising can be beneficial?
> and we know that two placebo sugar pills have a bigger effect than one, and that an intramuscular placebo injection is more effective than a placebo sugar tablet[...]
> And a four-way comparison, with either sugar pills or aspirin, in either unbranded aspirin boxes or mock-up packaging of the Dispirin brand, showed that brand-name packaging, and the wealth of advertising and cultural background material that packaging plays on, had almost as big an impact on pain as whether the pills had any drug in them. So in some ways, it's not irrational to believe that costly Nurofen is more effective than cheap unbranded ibuprofen, even if they've both got the same active ingredient.
https://www.theguardian.com/science/2004/apr/15/badscience.s...