> And a placebo controlled study is the best evidence for a medical treatment ...
Yes, and with respect to the drugs we're talking about, subsequent meta-analyses show that the original studies were all biased in favor of their sponsors and all the drugs produce the same results, which argues for a massive placebo effect.
For years, studies were published that appeared to support various drug approaches to mental illness, but those studies have been invalidated by more careful analysis that included (as just one well-known example) unpublished studies that came to conclusions not favorable to the drug companies' outlook.
> Consider an SSRI study for depression.
Yes, let's do that. As things stand right now, studies of drugs that increase serotonin levels show the same effects as those drugs that decrease serotonin levels. This causes open-minded scientists to doubt the efficacy of this entire approach.
Quote: "While S.S.R.I.s surely alter serotonin metabolism, those changes do not explain why the drugs work, nor do they explain why they have proven to be no more effective than placebos in clinical trials."
> I mean, the effects of SSRIs in healthy individuals is an interesting topic, but not relevant if I'm investigating depression treatments.
Such studies -- with the diagnosed depressed -- show no clinically significant result that can distinguish the outcome from the placebo effect. Those are the facts.
> For some commentators, the recent downfall of the chemical imbalance theory has cast doubt on the use of existing antidepressant drugs, which were meant to restore the lost serotonin. Yet the data certainly suggests that they work better than placebos
I would argue with this statement. Antidepressants don’t work better than active placebos like atropine that make you feel “something is different” like dry mouth or elevated heart rate.
> Recent research has indicated that Serotonin levels in depressed people are not lower than average. But SSRIs are effective for relieving depressive symptoms - either boosting serotonin levels above average works, or they work through some other pathway that hasn't been identified.
But that is exactly the point. If we don't know why something works, we can't even be sure that it does work.
Also SSRIs are only slightly more effective than placebo. [0]
Quote: "So, when we accessed the public domain data from the U.S. Food and Drug Administration (FDA) archives for the antidepressants approved between 1985 and 1997 (7), it quickly became apparent that many of the assumptions about the relative potency of antidepressants compared to placebo were not based on data from the contemporary trials but from an earlier era. Specifically, it became evident that the magnitude of symptom reduction was about 40% with antidepressants and about 30% with placebo."
Until/unless we can finally understand how the human endocrine system works, on both a broad statistical basis as well as on a predictable individual basis (i.e. in the same sense that statistically we know that X number of people die each year in automobile collisions but we don't know exactly WHICH people will die) we are making guesses.
The level of scientism our society exhibits - in which we cannot just accept that some things don't have answers that we can access at this time, and instead accept any answer "science" gives us - is unfortunate. Research we do is limited by what we look for, and the positivist approach we see in medicine ("Find diseases we can make money on") limits everything.
> Believe me, if there was a placebo-based solution to this, I would be the first person in line to get it...
If you are taking drugs for this, then you are in line already. Every one I have read about has studies showing it is only slightly more effective than placebos.
I really am not trying to say the problem is not real. I'm only saying that placebos are far more effective than you realize.
For example some quotes from wikipedia:
"Notably, however, a recent Cochrane review of the efficacy of the SSRIs concluded that they were only slightly more effective than placebo for the treatment of people with depression."
"A widely-reported meta-analysis combined 35 clinical trials submitted to the U.S. Food and Drug Administration (FDA) before licensing of four newer antidepressants (including the SSRIs paroxetine and fluoxetine, and two non-SSRI antidepressants nefazodone and venlafaxine). The authors found that although the antidepressants were statistically superior to placebo they did not exceed the NICE criteria for a 'clinically significant' effect. In particular they found that the effect size was very small for moderate depression but increased with severity reaching 'clinical significance' for very severe depression. The relationship between severity and efficacy was attributed to a reduction of the placebo effect in severely depressed patients, rather than an increase in the effect of the medication."
(Especially note the last sentence.)
Please don't understand this in reverse and assume people should/can do nothing. My point is placebos work, and people should make more use of them.
Another thing: just because something is all in your head does not mean it's not real. People often assume that "since a placebo fixed it, it was not real to begin with". NO! That's is NOT the case. The problem was REAL, and the placebo fixed it.
> Even WITH the unpublished studies included, the placebo effect far exceeds the required effect size to be considered clinically effective which means that the combination (placebo effect+treatment effect) also far exceeds the required effect size.
This is astonishing. The paper in question flatly contradicts you. The paper concludes, "antidepressant medications have reported only modest benefits over placebo treatment, and when unpublished trial data are included, the benefit falls below accepted criteria for clinical significance."
The above conclusion is not open to the interpretation you've given it.
And, in case you missed the train leaving the station, none of this will matter until some science is done -- science that uncovers the cause of depression and ends this guessing game and debating society.
> That's why it's normal these days, for clinical studies, for the control group to receive current best available treatment, rather than a placebo.
That's one of the reasons such studies are so unreliable -- they depend on a comparison of two or more drugs that may operate in different ways, rather than comparing a drug to the absence of a drug.
The result is predictable -- unbiased meta-analyses show that antidepressants don't work:
This is not to say that wouldn't have been the outcome anyway, regardless of the methods used, only that testing two drugs at once introduces confounding factors.
> We identified 28 552 citations and of these included 522 trials comprising 116 477 participants. In terms of efficacy, all antidepressants were more effective than placebo.
> We just have a currently useful tool to help, SSRIs.
Yes, but the quoted study shows that serotonin and depression aren't correlated. If that is so, if the study bears up under scrutiny, then SSRIs cannot possibly work. The prior FDA meta-analysis shows that SSRIs don't work for the majority of patients, this new study explains why.
> Maybe with these type of studies we'll see more accurate medicines.
Let me suggest an alternative -- instead of searching for a better description of depression, we should seek an explanation, like in science. Armed with an explanation, we could treat depression's causes, rather than its symptoms.
But we can't do this with psychiatry -- psychiatrists aren't scientists and have no respect for evidence.
>Antidepressants are supposed to work by fixing a chemical imbalance, specifically, a lack of serotonin in the brain. Indeed, their supposed effectiveness is the primary evidence for the chemical imbalance theory. But analyses of the published data and the unpublished data that were hidden by drug companies reveals that most (if not all) of the benefits are due to the placebo effect. Some antidepressants increase serotonin levels, some decrease it, and some have no effect at all on serotonin. Nevertheless, they all show the same therapeutic benefit. Even the small statistical difference between antidepressants and placebos may be an enhanced placebo effect, due to the fact that most patients and doctors in clinical trials successfully break blind. The serotonin theory is as close as any theory in the history of science to having been proved wrong. Instead of curing depression, popular antidepressants may induce a biological vulnerability making people more likely to become depressed in the future.
>It's shocking to me how few people realize that anti depressants very rarely outperform placebo
very rarely?
>Findings
>We identified 28 552 citations and of these included 522 trials comprising 116 477 participants. In terms of efficacy, all antidepressants were more effective than placebo ...
"I do know friends and family who have benefited from psychiatric medications, although that could entirely be due to placebo effect."
It isn't just you. EVERYONE knows people that have benefited from medication. I've seen people go from horrible, twisted states of mind turn into happy, functional people within months by taking medication. The idea that this is just a placebo effect is completely counter-intuitive, for too many reasons to list.
Don't believe for a second the idea that studies or science have anything to do with the author's opinion. People have been saying the same things ever since these medications were first released, without any facts or reasoning to back up their claims.
It isn't a surprise that after 30 years they've been able to come up with a couple of studies to back up what they're saying. What is surprising is that they'd be willing to ignore the tens of thousands of doctors all over the country that have seen these medications work, and the millions of people that have benefited from them. Studies have shown that about 75% of patients treated with antidepressants make a recovery. This is a miracle of modern medicine.
The idea that treating depression is a "loose and abstract field" is absurd. Millions of patients suffer from a range of similar systems. They get treatment, those symptoms are gone. There is nothing abstract about it. Yes, patients react differently to different medications, which is true for thousands of non-psychiatric conditions as well. In these cases, doctors also use trial and error.
Public figures against antidepressants are no better than Christian scientists who encourage patients not to seek treatment for cancer. They're also much more influential: they've persuaded hundred of thousands of people suffering from depression not to seek treatment.
> Now let's find out if this anti-depressant really helps anyone, or is it just another terrible drug with horrid side effects? If it doesn't help better than placebo; take it off the market?
The claim that SSRIs are no better than placebo is increasingly popular on the internet and among some researchers eager to make headlines, but the claim is not backed by the data. At best, it represents a misunderstanding of how the studies work, what they're showing, and how surprisingly effective placebo is in cases of mild depression.
> I do know drug companies have pretty much stopped all research in new anti-depressants. Why--they were caught with their pants down, lying, hiding bad studies, and fooling doctors and patients alike with their Slick claims.
This incident is deplorable and highlights a huge problem in our clinical trials process that needs to be addressed, but your extrapolations here not only don't make sense but they are flat-out incorrect.
There is quite a huge amount of research on new antidepressants. In the past few years alone we've added Vilazodone and Vortioxetine to our arsenal, both of which are primarily SSRIs but have some additional properties that might reduce the side effects due to requiring lower doses. We also have Levomilnacipran which is the first SNRI that favors norepinephrine over serotonin, which can be very helpful in some patients.
There are many interesting compounds in the pipeline as well, from rapid-acting compounds for addressing suicidal patients (ketamine infusion, esketamine nasal spray, GABA-A5 antagonists) to completely novel antidepressant compounds: opiod-modulating drugs like ALKS-5461 which have been very impressive in clinical trials, NMDA and sigma-1 antagonists, mGluR5 antagonists, NR2B antagonists, some very impressive BDNF modulators, anti-glucocorticoid strategies, and so on.
Contrary to your claims that "ruthless drug companies" have stopped all research, this is the most exciting time for anti-depressant research we've ever seen.
> all antidepressants were more effective than placebo
Comparing them to placebo isn't appropriate, you need to compare them with an active placebo and only look at studies that continue longer than two years. Of which there are all of like 2 studies.
> the most comprehensive review of the SSRI studies (by Irving Kirsch et. al.) found no clinical significance beyond placebo for the vast majority of patients.
No. Biological theories of mental health and mental illness are very much established.
And yours is a complete mischaracterization of the work of Kirsch et al.
Their meta-analysis found that in ALL cases of depression, there is statistically significant improvement in quantitative measures of depression treated with SSRI. In moderate to severe cases of depression, the improvement was clinically significant (ie a clinician and patient clearly note the improvement). The meta-analysis done on clinical trials were overwhelmingly trials of 6 weeks of SSRI or less. Suicidal patients are almost all excluded from such trials. Treatment groups were treated with SSRIs via research protocols, and not usual clinical practice: there were no attempts made to match patients to an SSRI that would be most likely to help, to wait on a response, to use SSRIs that were helpful based on a family history; dose adjustments were typically prescribed by study protocol and not by patient response, patients were not switched to another SSRI when there was no response or if intolerable side effects developed, often no attempt to treat side effects with other agents were done, etc. In other words, none of the things any physician routinely does to optimize treatment were done in those trials, and yet there were STILL improvements in measures of depression across the board.
No reputable psychiatrist or physician will fail to recommend an SSRI in cases of moderate to severe depression. Therapy can also be helpful, but the evidence is overwhelming that SSRIs help in clinically significant ways in moderate to severe depression. There is no credible doubt about it.
Despite your assertions about what "people very much want to believe" - in my experience, people very much want to believe that the brain is somehow different - that something beyond biology is at work. Believing that somehow depressed or otherwise mentally ill people can just "snap out of it" or "pull themselves up by their bootstraps" is erroneous, unhelpful, but fits nicely into really completely shitty and cruel narratives about human beings.
But please. Perhaps you'd like to advance a theory on how an organ like the brain differs from every other organ and does its work in ways not explainable by biology, chemistry, physics, etc.
> This latest research looked at 17 studies and found people with depression didn't appear to have different levels of serotonin in their brains to those without.
I think we are going no to look back in this and laugh and cry at how big of a mistake SSRIs were..
I think the body will find homeostasis. Artificially changing serotonin levels may have an effect for a while - but with continued administration the body will just create less naturally and become dependent on the drug for the remaining amount. So then after a while - everything went back to normal and in effect the only clinical result was a placebo effect, like the research suggests it’s efficacy is comparable to.
If there is some effect it is probably short term, which as the article points out, drug companies only like to study the short term effects (which still have debatable efficacy compared to placebo)
And what would this mean for the industry. They spent decades giving us the equivalent of sugar pills making billions of dollars. While we have already been in health care crisis.
Quote: "Meta-analyses of antidepressant medications have reported only modest benefits over placebo treatment, and when unpublished trial data are included, the benefit falls below accepted criteria for clinical significance." (emphasis added)
Translation: "If all legitimate scientific studies of antidepressants are examined at once, the outcome is that antidepressants do not work."
Analysis: The drug industry has funded many antidepressant studies over the years. Those that support the efficacy of antidepressants are published. Those that do not support the efficacy of antidepressants are not published. It's a simple, effective scheme, and until now it has worked -- most people think antidepressants work.
The study linked above did something clever -- they performed a meta-analysis of all the studies -- those that were completed and published, and those that were completed and then thrown away. The end result is that antidepressants do not work, i.e. are no more effective than a placebo.
But because practicing psychologists don't care about science, this study might as well not have been published -- it might as well have been thrown out along with the many studies that cast antidepressants in a bad light, studies that were suppressed.
Someday psychologists will be forced to adopt the evidence-based practice standards that govern the practice of medicine, but until that day arrives, they will continue to lie to their clients.
> Those graphs in the article look too close to placebo. So I wonder why antidepressants are still prescribed to treat any kind of disorder and not only, well, genuine psychogenic depression.
Another article goes deeper into this issue (ie. why do meta-studies show a statistically significant difference, but the difference is so small?)
This is not something you can claim. How could you possibly know that the SSRI is responsible for your recovery?
I'm not going to say that antidepressants are useless, but it is important to understand how placebo works. The key point is that placebo works and it is impossible for an individual to distinguish between a placebo and a life changing drug.
In antidepressant studies, SSRIs often outperform placebo to a degree. However, the placebo group has an excellent recovery rate! That means there are people who are clinically depressed, suicidal etc. who are then given a sugar pill as part of a study and make a full recovery.
>You often need to try 2 or 3 different SSRIs
That makes it even murkier. SSRIs take a long time to work, and if you try several of them that's going to take months to years. There's a high probability that in that time, you might naturally recover. You have the combined benefit of placebo and waiting in addition to the effects of the SSRI. You tried 2 SSRIs that didn't work. What makes you so confident that it was the third?
Again, I'm not saying SSRIs are useless. But it's important that we rely on controlled studies to make these determinations. Personal experience and anecdotes are beyond worthless; for example they are the reason why homeopathy is a $20 billion dollar industry even though it is actually provably useless.
> Your tl;dr for #2 isn't accurate. Yes, these medications "have reported only modest benefits over placebo treatment", but the measured benefit of placebo treatment in this case is quite large and the medications work BETTER than placebo.
Yes, unless unpublished studies are included in the analysis, after which the effect falls below that required to make a claim of clinical effectiveness. That distinction is perfectly clear in the post to which you replied.
> As for the claim that the difference falls below accepted criteria for clinical significance, the "accepted criteria" used to reach that conclusion are pretty arbitrary and it only just BARELY falls below the arbitrary level picked (by some), depending on which studies are included.
Weasel words, words that a scientist wouldn't dream of including in a study means to generate light, not heat. Which explains why this kind of argument is absent from the FDA study.
In any case, a more recent study quoted above finds no correlation between serotonin and depression. If this study bears up under scrutiny, it undermines the basis for SSRIs as a remedy for depression, for the simple reason that serotonin and depression have no relationship. It would explain why the statistics for SSRIs are so marginal -- what's being measured is a placebo response.
> Research suggests antidepressants work only a bit better than placebos
That really undermine the credibility of that article. They work extremely well for some people. Others might need to try several before they find one that works. And a minority might not be able to find one that works (I don't know, I'm not a professional).
Another anecdotal evidence: I started taking anti-depressants 1.5 months ago, and after the acclimating period (which was hell for me, I wish I had been better warned, I had to take a week off), it's a night and day difference on how my brain works.
My SO had the exact same experience: it changed her life, from a miserable struggle every day to a life she can enjoy.
If this article makes you reconsider taking anti-depressants or not, please talk to a healthcare professional instead.
Yes, and with respect to the drugs we're talking about, subsequent meta-analyses show that the original studies were all biased in favor of their sponsors and all the drugs produce the same results, which argues for a massive placebo effect.
For years, studies were published that appeared to support various drug approaches to mental illness, but those studies have been invalidated by more careful analysis that included (as just one well-known example) unpublished studies that came to conclusions not favorable to the drug companies' outlook.
> Consider an SSRI study for depression.
Yes, let's do that. As things stand right now, studies of drugs that increase serotonin levels show the same effects as those drugs that decrease serotonin levels. This causes open-minded scientists to doubt the efficacy of this entire approach.
Reference: http://www.newyorker.com/online/blogs/elements/2013/09/psych...
Quote: "While S.S.R.I.s surely alter serotonin metabolism, those changes do not explain why the drugs work, nor do they explain why they have proven to be no more effective than placebos in clinical trials."
> I mean, the effects of SSRIs in healthy individuals is an interesting topic, but not relevant if I'm investigating depression treatments.
Such studies -- with the diagnosed depressed -- show no clinically significant result that can distinguish the outcome from the placebo effect. Those are the facts.
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