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I think this should be investigated.The use of anti-depressants amount to performing medical experiments on people. E.g. Let's see this anti-depressant, then evaluate side-effects, if it doesn't work switch to different one or adjust the dosage. There is no scientific basis to do that. The supposed chemical inbalance is not being measured so the doctors really are giving people random drugs and those drugs are difficult to quit without medical supervision as well. When you quitting you feel so horrible you rather keep taking them. This is a huge money making racket for big pharma and make doctors look like charlatans at the same time casting doubts on medical profession. This only feeds to another camp like anti-vaxx.
Forgive me for being blunt, but that's just how modern medicine works. No one has the Star Trek tricorder that can scan your body, read your genome, and detect a quantum fluctuation in your synaptic waveform matriculation to calculate how many CCs to put in the hypospray.

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.

The situation is much worse than you outline, from a scientific perspective, and even well-meaning doctors aren't an antidote due to systemic distortions.

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.

The statistics don't support the use of anti-depressants in the majority of cases.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3736946/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4592645/

"that's just how modern medicine work"

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'd argue qualitative data is far more valuable than mass quantitative data, the problem is that's expensive and difficult to gather accurately - especially on a timescale that is longer than the only the 2 weeks that many if not all behaviour changing psychotropic medications required for 'adequate' research under heavily controlled environment before unleashing them onto the masses.

Statistics can point you into a direction, however it won't account for nuances in most or perhaps all cases.

Oh all of a sudden we should just accept some pathetically weak argument of "we just don't know". Billions at stake here and yes we can and will severely penalize anyone on the side of nonscience and profiteering where humans are harmed. We can do better. Sorry if it means consequences for certain people.
You're commenting on such an investigation. As for the try-and-evaluate method of matching antidepressants to patients, that is the best medicine has to offer right now. There's not a better way that they're choosing not to use, and the drugs do have measurable, significant benefits for patients once they find one or more that's effective for them. The "supposed chemical imbalance is not being measured" because that's more a figure of speech than a scientific theory, and there is no practical way to measure it and correlate it to mood imbalance, depression or other symptoms. What alternative do you propose?
Until recently, few pharmaceutical companies pre-registered antidepressant trials, which allowed them to selectively publish. This means that antidepressants may be nowhere near as effective as commonly believed, and so doctors are overweighting the benefits compared to the costs of side effects. .

“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.

For the last 40 years, people talked about psilocybin, weight lifting, lsd, fasting, meditation, wim hof and many other things that affect people's happiness.

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.

I had severe depression and I was a victim of such experiments. I lost two years of my life to these drugs and failed suicide two times at the end. What helped me get out of this mess was CBT therapy to change the way I think about things and how to deal with emotions, how to defuse going into the loops of sadness. I didn't need any drugs but doctors insisted it will make me feel better. Yes, I was feeling better initially - actually sometimes I could feel the effects to similar to those of cannabis. But after few months I was getting hallucinations, weird thoughts and sudden urges to kill myself. The doctors response was to change the dose or try different one. I think this should be illegal.
He is completely unaware that most(all?) those drugs can be easily quit if done very slowly.

He just wants a silver bullet.

Wow, where to start...

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...

Antidepressants are indeed effective, but those NNT numbers are based on outcomes (i.e. depression scores) that are more subjective and far more modest than the outcomes used to calculate NNT for things like aspirin or antihypertensives (cardiovascular events and/or death). I don't think they should be compared directly compared in that manner.

The NNT for antihypertensives to lower blood pressure is essentially 1, after all.

In a way, all drug usage is like performing experiments on people - some of them work better on certain people than others and some of them give terrible side-effects to some and not others. This isn't just true for anti-depressants.

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.

I agree with your overall message, but it's much more than a crappy week to come off of some commonly prescribed antidepressants. It takes months to taper off some of them safely.
A. There is no such thing as "chemical imbalance". B. Medicine is as much of an art as it is science (if not more of an art). C. Only some anti-depressants are the way you describe. The most promising anti-depressant, I.V. ketamine - acts rapidly, breaks through the most resistant depression is gone from your bloodstream within minutes/hours after infusion and there are zero withdrawal effects.
> There is no such thing as "chemical imbalance".

Why do many, many doctors say there is? It seems they, of all people, should know what they are talking about.

> B. Medicine is as much of an art as it is science (if not more of an art).

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?

You say "performing medical experiments" like it's a bad thing or there was some alternative, but life is usually lived based on empirical trial-and-error.

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.

About this:

“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.

> You are trying to disqualify clinical experience and an empirical approach, despite both being part of the Western scientific method for several centuries.

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.

I agree. Don’t forget about the negative environmental effects of the drugs as well. Fish become sterile i.e.[1]

[1] https://www.sciencealert.com/antidepressant-chemicals-are-ch...

For years I was told I was depressed and, as you described, “tried” one antidepressant after another. None of them helped with my symptoms (an otherwise healthy 20-something couldn’t get out of bed, sleeping constantly). It turned out I had lupus. I often wonder how many people who are being treated for depression have another illness entirely. I think a lot of times it’s just the best diagnosis currently available to many doctors.

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.

Yes, it is akin to randomly trying Game Genie codes.
My antidepressant is a generic, so drug companies are making hardly anything off me. That narrative doesn’t seem to fit.
No license to pay, huge volume plus overcharging the national healthcare provider?
> The supposed chemical inbalance is not being measured

I like the idea of measuring. How would we do it though?

I'm assuming it would involve a blender.
> Let's see this anti-depressant, then evaluate side-effects, if it doesn't work switch to different one or adjust the dosage.

Please tell us about the alternative treatment regimen you recommend, with references to the peer-reviewed, published literature supporting its efficacy.

On the other hand, sometimes there are significant differences between generic and brand name formulations. For example: https://www.fda.gov/drugs/postmarket-drug-safety-information...

I wonder how many patients had their complaints written off for the six years the generic was on the market?

Absolutely, even when the active compounds are the same but there are changes in composition.

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.

I wonder how many patients had their complaints written off for the six years the generic was on the market?

Or who didn't even bother reporting their complaints in the first place.

I'm a bit sceptical here. As it happens, my partner was taking Effexor (a branded formulation of venlafaxine) and was switched to the generic Enlafax. She complained to me that she was feeling a little bit worse starting around this point, and when patient groups started sharing stories of many people who began feeling worse following the switch (which is what led, eventually, to the media coverage), she requested switching back to Effexor (which required paying out of pocket, as it's no longer covered), resumed taking it, and started feeling better.

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.

The inverse is also true:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4172306/

Just goes to show how powerful the media is at shaping/controlling the individuals reality.

Where have I been that I'm apparently the only person in this thread who doesn't already know what "nocebo" means?
It's in the article:

"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"

It's the negative equivalent of a placebo. It usually manifests by patients experiencing the listed side-effects of a drug, even when given a placebo.
A bit of backstory:

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.

Except they used suicidal thoughts as their key symptom -- which is something that is widely already known to increase in prevalence with media attention, see: "13 Reasons Why"...
This article does not show any evidence of a nocebo effect. It shows increased reporting following publicity - without distinguishing whether the result was increased incidence of perceived harm, or just increased /reporting/ of perceived harm (for instance, if patients would not have previously attributed those somatic symptoms to their medication.)

Crap study, just an excuse for a publication.

This is also my take on this paper. It records an increase in reported side effects, which is not the same thing as an actual increase in side effects. Patients may have been experiencing these side effects anyway, but either didn’t report them, or didn’t associate them with the intervention.

Knowing these side effects are associated with the intervention would likely be enough for Confirmation Bias to increase the reported instance.

agree that it's crap study, but even worse than that it's an attempt to discredit symptom reporting in general

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

> ...people report a reduced therapeutic effect and more side effects from a generic-labelled placebo compared to a branded placebo

wa? the power of branding -- advertising can be beneficial?

Lots of things can influence the placebo effect, branding is one of them:

> 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...