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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 24 of 24. This is the beginning of the thread.
Posted by psychobot5000 on January 25, 2009, at 21:37:18
Title:
"Serotonin and Depression: A Disconnect between the Advertisements and the Scientific Literature"
by
Jeffrey R. Lacasse, Jonathan Leo*Here's the url:
http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1371%2Fjournal.pmed.0020392&ct=1This 2005 article politely lays into drug-advertising that pushes the Serotonin Hypothesis--I personally found it cathartic to read, given the way that paradigm has (counterproductively, in my opinion) dominated depression research until recently. I thought I'd post the link in case some of you might be interested and hadn't already seen it.
Posted by linkadge on January 26, 2009, at 8:17:04
In reply to Review Article Trashing Serotonin Hypothesis + Adv, posted by psychobot5000 on January 25, 2009, at 21:37:18
Good article
Linkadge
Posted by linkadge on January 26, 2009, at 8:18:09
In reply to Review Article Trashing Serotonin Hypothesis + Adv, posted by psychobot5000 on January 25, 2009, at 21:37:18
I still find the fact that *more* than half of all availalbe SSRI clinical trials fail to distinguish between SSRI and placebo distrbing.
Linkadge
Posted by Phillipa on January 26, 2009, at 12:16:07
In reply to Re: Review Article Trashing Serotonin Hypothesis + Adv, posted by linkadge on January 26, 2009, at 8:18:09
What I gained was the Fda does not regulate advertisements and there is no proof that serotonin is deficient in brain in humans and how do you measure serotonin in the cerebral spinal fluid. And that CBT is overlooked. That was my take? Phillipa
Posted by psychobot5000 on January 26, 2009, at 15:53:09
In reply to Re: Review Article Trashing Serotonin Hypothesis + Adv, posted by linkadge on January 26, 2009, at 8:18:09
> I still find the fact that *more* than half of all availalbe SSRI clinical trials fail to distinguish between SSRI and placebo distrbing.
>
>
> LinkadgeI partly agree, but I think it might be more accurate (and less disturbing) to say that 57% (or so) of available trials weren't able to come up with a -statistically significant- difference in the results between them. Depression is a tough illness, I figure, and these statistically driven trials seem a fairly crude method to use for research. Or they do to me, anyway. I would hope that part of the problem is with the -precision- of placebo-controlled trials, rather than the inefficacy of the treatments available (though obviously that is also an issue). So I hope.
Psychbot
Posted by linkadge on January 26, 2009, at 18:06:41
In reply to Re: Review Article Trashing Serotonin Hypothesis + Adv » linkadge, posted by psychobot5000 on January 26, 2009, at 15:53:09
But, if the SSRI's are really no better than placebo, thats what you would statistically expect - that fewer than half of studies find them better.
Even if SSRI's were exactly equivilant to the placebo, you'd still expect approximately half of studies indicating they're better, and the other half indicating they're not.
Linkadge
Posted by seldomseen on January 26, 2009, at 18:23:45
In reply to Re: Review Article Trashing Serotonin Hypothesis + Adv, posted by linkadge on January 26, 2009, at 18:06:41
That would only hold true if the studies were conducted on exactly the same population and in the exact same manner.
I doubt that's the case with the SSRI studies.
Now, I'm not saying that there isn't a high placebo response rate in psychiatric studies - there is.
Posted by seldomseen on January 26, 2009, at 18:40:34
In reply to Review Article Trashing Serotonin Hypothesis + Adv, posted by psychobot5000 on January 25, 2009, at 21:37:18
I can see why this article would be cathartic to read. I think the author's primary contention is not that the serotonin hypothesis is necessarily wrong (it may be, it may not be), but that it is unethical to use a hypothesis to sell drugs.
I especially liked the illustration that if a rash on one's arm is cleared up with a steroid cream, does that mean that one is deficient in steroids? Good stuff, really good stuff there.
Seldom
Posted by Larry Hoover on January 27, 2009, at 7:08:56
In reply to Re: Review Article Trashing Serotonin Hypothesis + Adv, posted by linkadge on January 26, 2009, at 18:06:41
> But, if the SSRI's are really no better than placebo, thats what you would statistically expect - that fewer than half of studies find them better.
>
> Even if SSRI's were exactly equivilant to the placebo, you'd still expect approximately half of studies indicating they're better, and the other half indicating they're not.
>
> LinkadgeNo, link, there's more to it.
If antidepressants were really no better than placebo, you'd find that placebos were just as frequently superior to antidepressants, and by similar amounts. About 90% of studies would show no superiority of either study arm (no significant difference), and 5% would show significant antidepressant or placebo superiority.
Lack of significant superiority of antidepressants over placebo occurs in about half of trials. That's not the same thing as saying there's no difference. There is virtually always a superior response to antidepressants, but half the time it's not strong enough to reach signficance.
Lar
Posted by Larry Hoover on January 27, 2009, at 7:20:22
In reply to Re: Review Article Trashing Serotonin Hypothesis + Adv » linkadge, posted by Larry Hoover on January 27, 2009, at 7:08:56
"About 90% of studies would show no superiority of either study arm (no significant difference), and 5% would show significant antidepressant or placebo superiority."
Errr, I should have my coffee before I post about this stuff. The numbers should read 95%, 2.5% and 2.5% (two-tailed test of significant difference). If your hypothesis was strictly defined to test only whether placebo was superior to antidepressants (one-tailed test), and the two were actually equivalent, you'd find that placebos were superior 5% of the time (and 1% of the time vastly superior, with p < .01), and 95% of the time there'd be no difference.....in a purely theoretical world.
Just in case anybody's noticing, the data do not show anything like that.
Lar
Posted by Larry Hoover on January 27, 2009, at 10:18:45
In reply to Review Article Trashing Serotonin Hypothesis + Adv, posted by psychobot5000 on January 25, 2009, at 21:37:18
I finally had time to read the paper, and if I was grading it, I'd give it at most a B-.
The big problem is the recurrent conflation between two separate concepts, serotonin deficiency and chemical imbalance. They're not interchangeable concepts, and yet they treat them as if they are. In some cases, they appear in sequential sentences. By the time you're finished reading the paper, this deliberate blurring of meaning allows for conclusions not supported by the evidence provided.
Now, I'm not supporting the pharmaceutical advertisements literally, but given that mental illness remains heavily stigmatized, and that only 30% of depressed individuals obtain treatment for it, I think that anything that gets people to see their doctors is a good thing. A doctor prescribes not because a patient claims chemical imbalance, but because an examination and medical history yields a clinical diagnosis that may benefit from treatment.
The selective use of evidence also struck me. For example, reference 46 is supplied to show that patients are reporting that they have a chemical imbalance, when the article actually discusses the evolution of conceptual modelling about pharmaceutical treatment of depression. To quote therefrom:
"What these drugs do is affect receptors. Instead of being concerned about the effect of norepinephrine and serotonin, we really need to redefine our concept of psychopharmacology as receptor drugs. Saying, for example, that selective serotonin reuptake inhibitors (SSRIs) treat depression by increasing serotonin is like saying that a boat sinking on the ocean needs to have reduced water levels. The water is there and all around. To fix the boat you need to plug the holes. That will be a great deal more effective than worrying about decreasing the overall amount of water in the system.... Once we begin to conceive of drugs as affecting receptors, things generally seem to make more sense."Lar
Posted by linkadge on January 27, 2009, at 10:59:37
In reply to Re: Stats...ooops, posted by Larry Hoover on January 27, 2009, at 7:20:22
I am not sure I follow you. Didn't the meta analysis compare the number of studies in which SSRI's were superior to placebo to the number of studies in which SSRI's are inferior to placebo. I don't understand statistical significance in this context. In any given clinical trial, the rate of active drug responce is either higher or lower than the placebo responce.
Linkadge
Posted by psychobot5000 on January 27, 2009, at 11:33:00
In reply to Re: Review Article Trashing Serotonin Hypothesis + Adv, posted by Larry Hoover on January 27, 2009, at 10:18:45
> I finally had time to read the paper, and if I was grading it, I'd give it at most a B-.
>
> The big problem is the recurrent conflation between two separate concepts, serotonin deficiency and chemical imbalance. They're not interchangeable concepts, and yet they treat them as if they are.
>I'd say that's true. However, isn't this conflation largely the fault of the advertisers they're covering? It seems to me that when 'chemical imbalance' is mentioned in reference to depression...the speaker (prescribing physicians and drug company reps etc) is almost inevitably talking about serotonin. Reading the paper, I understood immediately how the two concepts are frequently conflated. Now, granted, the authors of this paper don't actually make the point, instead seeming to conflate them themselves, which weakens their argument. But still, because of common assumptions about this in the medical community, I don't think the terms 'chemical imbalance' and 'serotonin deficiency' are actually very distinct the way they're used in practice (in reference to unipolar depression, at least). When someone says 'chemical imbalance'...everyone knows what chemical they're talking about. ...However, obviously the paper needed to do better work laying that out and not smooshing it all together themselves.
> Now, I'm not supporting the pharmaceutical advertisements literally, but given that mental illness remains heavily stigmatized, and that only 30% of depressed individuals obtain treatment for it, I think that anything that gets people to see their doctors is a good thing. A doctor prescribes not because a patient claims chemical imbalance, but because an examination and medical history yields a clinical diagnosis that may benefit from treatment.
>Hmm. That is a good point. I'm not against drug advertising either. However, here's one problem (in my view). I've talked with psychiatrists and psychiatric NPs who, based on the idea of a 'chemical balance' which I imagine they got from some combination of hopeful theorizing, direct-to-physician advertising, and conventional wisdom within the medical establishment, will refuse to prescribe -anything- -but- SSRIs. If you finished all four or five or six that were on the market without an adequate response, well then it was time to start over with the first one, which 'might work this time around.' ...Seems to me that the serotonin paradigm distorts prescriber practices, preventing them from using more effective 2nd and 2rd and 4th line treatments, and that to-physician advertising mirrors to-patient advertising. The former may distort physicians' understanding of the illness, and their understanding of how it ought to be treated. Through this, it also ends up marginalizing patients who -don't- respond to SSRIs (or those who can't tolerate them). Granted, advertising to (and group-think among) physicians, is outside the scope of this article. But I think it's all connected.
Merely a few quibbles. Good points, nice analysis.
Psychbot
Posted by Larry Hoover on January 27, 2009, at 17:59:31
In reply to Re: Stats...ooops, posted by linkadge on January 27, 2009, at 10:59:37
There are two sequential statistical procedures used in this sort of study. You calculate the average change resulting from the drug and placebo groups, and then you determine if the difference between groups (if any) is large enough to be unlikely to have occurred by chance.
Here is an image showing difference in mean change between the drug and placebo arms from the published and unplished antidepressant trials recently studied by Kirsch:
The zero line across the chart indicates no difference between the groups. Plots below the zero line indicate that placebo was superior. Plots above the zero line indicate that the drug was superior. Don't be confused by the dark horizontal line at 3. That's not relevant at this point. What is very clear is that far more often than not, drug response was superior to placebo, in absolute terms.
The second step is to determine if the difference is significant. That's really an unfortunate choice of language, because it has nothing to do with how meaningful the difference is. What significance means is nothing more than determining if the observed difference in group means is or is not likely to be due to chance, with typical significance thresholds set at 5% or less that chance findings explain the difference.
The basic assumption in all such studies is that there is no difference. That's called the null hypothesis. In order to reject the null hypothesis, calculated differences in group means must exceed a specific threshold, taking into account variability in the size of the groups, and the variability in scores within each group. There are tables of standard values with thresholds for 95% and 99% probabilities that the observed difference is a true difference, for different sizes of groups.
This article references an earlier Kirsch meta-analysis, using most of the same data as the table I provided, which found that 57% of the time the difference between the placebo and drug response was not large enough, taking into account the size and variability in individual response within the two groups, to reach the threshold required to reject the null hypothesis. If you go back to that image I linked to earlier, now that line at 3 has meaning. It is a slightly different representation of the threshold of statistical significance, but it's similar enough. Above that line, the difference is significant, i.e. drug was better than placebo, with strong likelihood that the observed difference is not due to chance (I count 16 such studies). There are no studies in which the contrary finding is true, i.e. no studies indicated that placebo was superior to drug (nothing below -3). For all the rest, those below the line at difference = 3 and above difference = -3, the null hypothesis was not rejected. For those studies (57% according to Kirsch), the assumption that there was no difference is not invalidated STATISTICALLY. The chart clearly shows otherwise, IMHO, but not to the standard required by science.
Here's a link that shows graphical representations of the influence of within-group variability on the test for a significant difference between two groups:
http://www.socialresearchmethods.net/kb/stat_t.phpIt doesn't matter if you use a t-test, as the latter link demonstrates, or ANOVA. The results should be identical.
Lar
Posted by Larry Hoover on January 27, 2009, at 18:20:16
In reply to Re: Article--Serotonin Hypothesis and Advertising » Larry Hoover, posted by psychobot5000 on January 27, 2009, at 11:33:00
> > I finally had time to read the paper, and if I was grading it, I'd give it at most a B-.
> >
> > The big problem is the recurrent conflation between two separate concepts, serotonin deficiency and chemical imbalance. They're not interchangeable concepts, and yet they treat them as if they are.
> >
>
> I'd say that's true. However, isn't this conflation largely the fault of the advertisers they're covering?I don't think so. I remember a Time magazine article from circa 1987 that presented pretty much that same argument for Prozac. It's pretty much what I'd call popular culture.
> It seems to me that when 'chemical imbalance' is mentioned in reference to depression...the speaker (prescribing physicians and drug company reps etc) is almost inevitably talking about serotonin.
....according to popular culture. I don't think the drug companies have done anything more than tap into that pop culture understanding.
> Reading the paper, I understood immediately how the two concepts are frequently conflated. Now, granted, the authors of this paper don't actually make the point, instead seeming to conflate them themselves, which weakens their argument.
That is precisely what I was trying to get across. These authors needed to rigorously distinguish the two, and maintain distinct lines of argument. They did the same thing they're criticizing others for doing. There is one example (Table 2) from a 1998 ad for Prozac that alludes to the level of serotonin dropping, but nothing recent comes close to that. They seem to want to criticize current advertising practise, while relying on a very dated hypothesis, and one modestly ancient advert for their negative evidence.
> But still, because of common assumptions about this in the medical community, I don't think the terms 'chemical imbalance' and 'serotonin deficiency' are actually very distinct the way they're used in practice (in reference to unipolar depression, at least). When someone says 'chemical imbalance'...everyone knows what chemical they're talking about. ...However, obviously the paper needed to do better work laying that out and not smooshing it all together themselves.
Yup.
> > Now, I'm not supporting the pharmaceutical advertisements literally, but given that mental illness remains heavily stigmatized, and that only 30% of depressed individuals obtain treatment for it, I think that anything that gets people to see their doctors is a good thing. A doctor prescribes not because a patient claims chemical imbalance, but because an examination and medical history yields a clinical diagnosis that may benefit from treatment.
> >
>
> Hmm. That is a good point. I'm not against drug advertising either. However, here's one problem (in my view). I've talked with psychiatrists and psychiatric NPs who, based on the idea of a 'chemical balance' which I imagine they got from some combination of hopeful theorizing, direct-to-physician advertising, and conventional wisdom within the medical establishment, will refuse to prescribe -anything- -but- SSRIs. If you finished all four or five or six that were on the market without an adequate response, well then it was time to start over with the first one, which 'might work this time around.' ...Seems to me that the serotonin paradigm distorts prescriber practices, preventing them from using more effective 2nd and 3rd and 4th line treatments, and that to-physician advertising mirrors to-patient advertising. The former may distort physicians' understanding of the illness, and their understanding of how it ought to be treated. Through this, it also ends up marginalizing patients who -don't- respond to SSRIs (or those who can't tolerate them). Granted, advertising to (and group-think among) physicians, is outside the scope of this article. But I think it's all connected.I suspect that the practictioners you speak of here are of a certain age.....there seem to be persistent patterns of prescribing based on med school training/early professional practises. I had a pdoc who only prescribed tricyclics and trazodone. He had grey hair, too. ;-)
> Merely a few quibbles. Good points, nice analysis.
>
> PsychbotThanks. Yours too.
Lar
Posted by Larry Hoover on January 28, 2009, at 8:32:33
In reply to Re: Stats...ooops, posted by linkadge on January 27, 2009, at 10:59:37
There's another way you can visualize what I'm trying to describe. Again, it starts with the data in this slide:
http://medicine.plosjournals.org/perlserv/?request=slideshow&type=figure&doi=10.1371/journal.pmed.0050045&id=96831&ct=1You can plot your own histogram (bar graph) from this data set.
If the two comparator groups, drug and placebo, are not different, then a histogram of their difference in mean scores should yield that classic bell curve, with the peak of the curve at or near the zero line, which is called the normal distribution. If you create this histogram, the x axis should have the range of -10 to + 10, and the y-axis should the number of trials at each unit interval. Estimates are fine. You don't need to be perfect.
If you do that, you get nothing at all like the classic bell curve. Instead, you get something more or less like half of a bell curve. The data are said to exhibit homoskedacity, which is to say they are skewed or biased (-skedacity part) in one direction (the homo- part). In all my years of studying stats and such, I doubt I've ever seen such a classic example of this type of distribution.
Also, in a normal distribution, only 2.5% of the data points should lie so far above the zero difference point that they are considered to be significantly different from the rest. In this example, we have 43% (i.e. 100% minus 57%) which are significantly above the zero difference line.
And yet, with this overwhelming evidence of drug superiority, critics use sophistry to declare things like "80% of the response of drugs is seen in the placebo group". But that's due to confounding variables, uncontrolled independent variables, in the clinical trial methodology. If the critics were intellectually honest about the findings, they would be criticizing clinical trial methodology, not the drugs.
In my perhaps not so humble opinion.
Lar
Posted by SLS on January 28, 2009, at 8:58:22
In reply to Re: Stats...ooops » linkadge, posted by Larry Hoover on January 28, 2009, at 8:32:33
Hi Larry.
How do you interpret the dashed line representing "Very Severe Only"? What are its implications regarding study design?
Thanks.
- Scott
Posted by Larry Hoover on January 28, 2009, at 10:20:17
In reply to Re: Stats...ooops » Larry Hoover, posted by SLS on January 28, 2009, at 8:58:22
> Hi Larry.
>
> http://medicine.plosjournals.org/perlserv/?SESSID=117d5ff3d1cfb7ab00f072415cdba934&request=slideshow&type=figure&doi=10.1371/journal.pmed.0050045&id=96831
>
> How do you interpret the dashed line representing "Very Severe Only"? What are its implications regarding study design?
>
> Thanks.
>
>
> - ScottThe different slopes of the regression lines are likely due to the inclusion or exclusion of the one study way to the left, where initial Hamilton Depression scores were less severe. Critics of antidepressant drugs argue that the implication is that the drugs are unnecessary or ineffective for mild to moderate depression. In fact, the likelihood of placebo response is inversely correlated with initial severity of depressive symptoms. In effect, it is more likely to mask drug response in those with lesser severity. If you plot drug response alone against HRSD, the line is virtually horizontal, indicating stable response across initial severity.
Over time, placebo response in antidepressant clinical trials is increasing. What that indicates, IMHO, is that we are becoming better at treating depression overall. The uncontrolled independent variables that promote placebo response, the caring expert physician (run of the mill family doctors don't participate....it's the cream of pdocs, typically), regular and detailed follow-up (weekly or biweekly), the symbolism of being in a clinical trial (expectation of better treatment than is otherwise available), co-morbidities excluded, brief duration, and so on.
I don't know that study design needs to change. I think interpretation needs a shake-up. Getting hung up on statistical significance or the magnitude of difference scores is an overly restrictive viewpoint. Clinical trials do not represent typical clinical practise. If a drug surpasses placebo despite the artificial circumstances, it is a true difference. Failure to find a significant difference does not mean there isn't one. The homoskedacity (see my post immediately prior to this one) in clinical trial outcomes has only one reasonable interpretation.
You're welcome.
Lar
Posted by psychobot5000 on January 28, 2009, at 14:51:39
In reply to Re: Stats...ooops » Larry Hoover, posted by SLS on January 28, 2009, at 8:58:22
Hey Scott,
Re: another question you seemed to have a few days back--if you wanted to switch your babblemail on briefly, there's a link I could send you.
Psychbot
Posted by SLS on January 28, 2009, at 17:56:26
In reply to (for SLS), posted by psychobot5000 on January 28, 2009, at 14:51:39
> Hey Scott,
>
> Re: another question you seemed to have a few days back--if you wanted to switch your babblemail on briefly, there's a link I could send you.
>
> Psychbot
Ok. I think I'm on.
- Scott
Posted by SLS on January 28, 2009, at 18:29:53
In reply to Re: Stats...ooops » SLS, posted by Larry Hoover on January 28, 2009, at 10:20:17
What are we treating?
It has been a contention of mine that the inclusion criteria for antidepressant trials is too broad - that is, if one is testing the efficacy of drugs to treat Major Depressive Disorder. I feel that too many studies allow for psychogenic or situational depressions to get through - mostly with "mild-to-moderate" depressions. Limiting inclusions to people with depression scores in the severe range promotes a greater likelihood that one is looking at true MDD. In such studies, active compound separates from placebo by a very large margin. It is quite convincing.
This is not to say that MDD does not include mild to moderate presentations. It does. They just get lost in the pool of non-biological depressions. I believe that non-biological depressions are much more apt to respond to placebo than biological depressions, especially with the extra care, attention, promise, and hope that is presented to them in a clinical trial.
Without greater diagnostic specificity, biomarkers would be the only way to separate out Major Depressive Disorder from other types. So... until then, selecting the more severe cases increases the percentage of biological depressions being tested.
There. I said it.
I'm ready for the wet noodle.
Oh, before I forget. Crap. I forgot.
Oh, well. It will come to me. Maybe next time.
Oh, yeah. I bet if clinical trials were allowed to run for more than 6 weeks, many of your placebo responders would "relapse", thereby separating active compound from placebo by a larger margin at the completion of the study.
I have no statistical background, so I must rely on intuition. Lame, I know. I understand much of what you explain, but without having the tools myself, I cannot analyze things from the same perspective on my own. Thanks for all your help.
- Scott
Posted by Larry Hoover on January 29, 2009, at 7:55:44
In reply to Re: Stats...ooops » Larry Hoover, posted by SLS on January 28, 2009, at 18:29:53
> Oh, yeah. I bet if clinical trials were allowed to run for more than 6 weeks, many of your placebo responders would "relapse", thereby separating active compound from placebo by a larger margin at the completion of the study.
They do have some data on that. There are two words they use for it, and I can only think of one. A continuation trial is what you're looking for, if you want to do a keyword search. I also recall perhaps two meta-analyses of continuation trial data. Again, if I recall correctly, placebo responders are well over twice as likely to relapse, and to relapse sooner than medication responders.
> I have no statistical background, so I must rely on intuition. Lame, I know. I understand much of what you explain, but without having the tools myself, I cannot analyze things from the same perspective on my own. Thanks for all your help.
>
>
> - ScottYou're welcome for the help. I don't mind contributing whatever I can. I know we have an audience, so I try to speak to the whole. I try to be thorough without being overwhelming. Whenever I can find an opportunity, I try to explain concepts in more than one way.
Over time, with practise, you get better and better at it. I can eyeball a chart and get a feel for what the stats should be like, but that wasn't always the case, certainly. It does get my gall up when I see someone using selected statistics to misrepresent a dataset. I try to be balanced in my responses, but I fear my emotion makes me appear overzealous. Anyway, now I'm way off on a tangent.
Take care,
Lar
Posted by antigua3 on January 29, 2009, at 10:57:30
In reply to Re: Stats...ooops » SLS, posted by Larry Hoover on January 29, 2009, at 7:55:44
I think you're great and do a wonderful job explaining things to the best of your abilities, which far exceed mine! I've learned a lot from you and I appreciate the effort you make for the whole community here.
antigua
Posted by Larry Hoover on January 29, 2009, at 11:33:21
In reply to Re: Stats...ooops » Larry Hoover, posted by antigua3 on January 29, 2009, at 10:57:30
Thank you.
Lar
This is the end of the thread.
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