![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 16 of 16. This is the beginning of the thread.
Posted by Netch on February 26, 2008, at 4:48:17
"According to new research from Britain, new generation anti-depressants could be for many patients a waste of time and money and offer little clinical benefit.
Scientists from Hull University carried out an analysis of a 47 clinical trials involving five thousand patients with depression and found that most widely-prescribed anti-depressants work little better than dummy pills.The antidepressants - Selective Serotonin Reuptake Inhibitors (SSRI) - which were studied included Prozac, Seroxat and Efexor and were found to be little more effective than placebos in improving the mental health in the majority of cases.
The new research found that the most widely prescribed anti-depressant pills are ineffective and only in the most extreme cases of depression did the tablets prove substantially superior in improving mental health.
Lead researcher Professor Irving Kirsch says the difference in improvement between patients taking placebos and patients taking anti-depressants is not very great, which means that depressed people can improve without chemical treatments."
http://www.news-medical.net/?id=35583
/Netch
Posted by dbc on February 26, 2008, at 5:28:02
In reply to ADs found to offer little clinical benefit, posted by Netch on February 26, 2008, at 4:48:17
We were talking about this on somethingawful. The general consensus was that they cherry picked what statistics supported their hypothesis and that it hasnt been peer reviewed.
Its like those studies that prove smoking is healthy.
Posted by yxibow on February 26, 2008, at 5:45:35
In reply to Re: ADs found to offer little clinical benefit, posted by dbc on February 26, 2008, at 5:28:02
You know... oh dear... this is going to go close to a PBC thread...
http://www.guardian.co.uk/news/2006/apr/01/mainsection.guardianletters1#article_continue
It is probable that Kirsch has some views that lets say... that borderline q****
and this is coming from the esteemed University College London Pharmacology department
http://www.ucl.ac.uk/Pharmacology/dc-bits/quack4.html
If not dozens of people on here are living proof that medication provides some -- and I do emphasize some (if medicine X relieves symptom Y 30-40% of the time, you're doing quite well) -- relief of symptoms -- remember, we are still living in the earliest stages of unraveling everything about the brain, then I don't know what to say.
I know that Luvox is doing something for me and I believe that over time so has Lamictal actually possibly had an impact as well.
I personally think it does a disservice and discouragement on the -medication- board as opposed to alternative ideas, to illustrate broad negative generalizations, but one is free to have freedom of thought.
Posted by Phillipa on February 26, 2008, at 13:19:10
In reply to Re: ADs found to offer little clinical benefit, posted by yxibow on February 26, 2008, at 5:45:35
Low dose luvox does something what don't know for me. Phillipa
Posted by Reggie BoStar on February 27, 2008, at 0:22:26
In reply to Re: ADs found to offer little clinical benefit, posted by yxibow on February 26, 2008, at 5:45:35
Now Time Magazine is running this one on the spin machine. Here it is:
http://www.time.com/time/health/article/0,8599,1717306,00.html
In these sorts of situations it's very difficult for me to separate the players from the actual data.
One side says their data is valid and previous studies are somehow lacking or flawed. Another side says the same thing about their data, with perhaps a twist to the effect that more recent studies need to be taken into account.
It's all Deja Vu for me, for almost 15 years now. The folks at the extremes have always been so biased that I don't trust any of their interpretations of the data.
I'm sure there is some valid data somewhere that's meaningful; but I doubt we'll ever hear of it. There are just too many different interests all normalizing the data in different ways.
Here's what I trust. I trust me. Whenever I start a new drug for any condition - not limited to depression - I remind the caregiver that there can be no placebo effect with me.
This isn't a boast at all. My attitude about any and all attempts to fix whatever's wrong with me is that they will fail. This is just a symptom of my flavor of depression and has been present since I was 10 years old. I'm now 56. It hasn't changed one iota in all that time.
For this reason I've been through a lot of medications, especially antidepressants. I started on Prozac in its very early days. There seemed to be some positive effects at first, but they disappeared over the course of a few months. Present always was my conviction that "even if this gets any better, it won't last".
I then cycled through just about all the SSRIs with the same or similar results (when Paxil failed, it was a CRASH). Until some the SNRI's started coming out, I saw no sustained relief to the point where I could at least manage my depression.
It turned out that SNRIs have the right combination of neurotransmitter tweakers to get me out of bed and out of the house. I'm not happy about doing that - far from it - but at least I'm getting out.
And with me, that's a real, measurable effect. That's because, as always, I don't expect it to last. Now I've been on Cymbalta for over 2 years and it's hanging in there. I can therefore trust myself enough to say that SNRIs do have an effect on me, and it's not negative, and it's lasted for a few years; i.e., so far it works and all the controversy that comes and goes over these things has nothing to do with it.
Since Prozac other medications besides SNRIs have been developed. These include Neurontin (Gabapentin) and Gabitril which mimic the action of the neurotransmitter GABA (gamma-aminobutryc acid); and the Triptan drugs which stimulate Serotonin production by binding to 5-HT* sites.
The resulting effects for me are:
1. Daily intake of the GABA simulators has dramatically reduced the number of migraines I get.
2. Even if I do get a migraine now, a Triptan drug such as Imitrex or Maxalt actually aborts the attack within an hour.I know these work for the same reason I trust myself to identify other meds that work without a placebo affect. I never believe they're going to work. This to some degree is how migraines affect me during attacks. Despite what I know about them, I'm absolutely convinced that an attack will never end. Migraines just affect my thinking that way, among all the other awful things they do.
So: as far as I'm concerned, the SSRIs which don't work at all for me have led to the development of other meds which help me function at least a little (Cymbalta) and which can reduce the number of migraines I get (Neurontin/Gabapentin) and stop the ones I do get (Imitrex/Maxalt).
The SNRIs have a ways to go because Cymbalta's action on me is minimal. But it's a start.
This is why I don't care much what the media hollers about this stuff from time to time. To me it's all sensationalism and is in the same class as the Britney-mongers.
This is just my case though and how these things work or don't work for me. Other folks are no doubt having different experiences. I hope they're good ones.
Reggie BoStar
Posted by Jay_Bravest_Face on February 27, 2008, at 5:01:00
In reply to Re: ADs found to offer little clinical benefit » yxibow, posted by Reggie BoStar on February 27, 2008, at 0:22:26
Well, my take and experience (15 years or so) is that over time and with experiments, YES, medications CAN and DO work.
When I first started on meds, a tiny dose of a Elavil and Ativan was tossed at me, and of course it did very little. Then the SSRIs where big, and I tried, and they did a little bit more, but not much. Then the SNRIs, first generation like Effexor, and did more, but still not enough. Then many combos, with my bipolar diagnosis, and mood stabilizers, and still no go. And, modern day, we are working with a new generation SNRI, Cymbalta, and a dash of older Prozac, plus Risperdal for mood stabilization and Topamax as well..oh and clonazepam, and I have really been seem to be doing fine.
Somedays better then others, but heythat is fine by me. It beats the bad old days where I didnt know what to expect one hour to the next!I am currently rebuilding my life, and take care not to make too much stress, but handle stress like a normal person. When I overload with stress, I go lay down or have a bit of a nap with a clonazepam. But, I work really hard on it, and it does pay off.
Life is getting better, and that is what counts. Quite a bit of thanks to Science and Medications.IMHO.
Ja
Posted by Cecilia on February 27, 2008, at 5:17:04
In reply to Re: ADs found to offer little clinical benefit » yxibow, posted by Reggie BoStar on February 27, 2008, at 0:22:26
The thing I've never understood is WHY AD's have such a high rate of placebo response. I would think most depressed people would be more like me, NOT expecting the drug to work, an anti-placebo response, That's the nature of depression, and unfortunately for me has always proved true.
The trouble with all the studies of course, is that there are probably many types of depression, some psychologically caused, some physiologically caused, some a combination. The studies act like they're all the same, no wonder they get such mixed results. It's like putting people with a cough into one study, without differentiating whether they've got TB, asthma, pertussis, allergies, lung cancer or the common cold. Cecilia
Posted by Netch on February 27, 2008, at 7:02:43
In reply to Re: ADs found to offer little clinical benefit, posted by Cecilia on February 27, 2008, at 5:17:04
Sometimes I get the feeling many drugs success and profits come at least partially from placebo effects.
/Netch
Posted by Dopamine123 on February 27, 2008, at 10:41:54
In reply to Re: ADs found to offer little clinical benefit, posted by Cecilia on February 27, 2008, at 5:17:04
http://www.slate.com/id/2182585
"In the rush to bring patented compounds to market, pharmaceutical houses sometimes enroll research subjects who barely meet criteria for the condition under study (in this case, depression). In some early trials, researchers may purposely use low doses; the idea is to squeak by the FDA's minimum efficacy requirements without raising concerns about side effects. Because the subjects do not have the relevant disease, and because normal people's moods wax and wane, these sloppy studies have high placebo response rates. The subjects simply look better over time. And because people without depression (or depressed people on too little drug) may not respond to the medication being tested, true effects are muted. Instead, the study shows an elevated placebo response rate. And then the research tends not to get published, because it's simply not credible."
Posted by Sigismund on February 27, 2008, at 18:23:23
In reply to Re: ADs found to offer little clinical benefit, posted by Dopamine123 on February 27, 2008, at 10:41:54
I'd like to be able to say that I've got more out of medications than they've got out of me, but I can't.
Posted by Phillipa on February 27, 2008, at 18:43:07
In reply to Re: ADs found to offer little clinical benefit, posted by Sigismund on February 27, 2008, at 18:23:23
Only ones that helped me were and are still benzos and at this period of my life pain meds for a short time anyway. Hence as I've said from day one and all my docs agree benzos are for my diagnosis anxiety panic and social. Three months after I was put on ad's had to stop working. So for me personally they do not work and if anxiety is under control feel pretty good. Other factors in my case to consider are the levels of stress in my life at the time. When life is flowing. l smoothly I'm fine and have been totally med free. Now this is just me. Phillipa unfortunately I will need a low dose of luvox probably for a long time. Thankfully I dropped down after a few weeks on high doses docs idea when asked him why he was cutting down the ad he said cause you were only on high doses as you were in the hospital. Justification for insurance at the time. When I think of the money I've spend.
Posted by yxibow on February 28, 2008, at 8:08:39
In reply to Re: ADs found to offer little clinical benefit, posted by Netch on February 27, 2008, at 7:02:43
> Sometimes I get the feeling many drugs success and profits come at least partially from placebo effects.
>
> /NetchIf a medication doesn't have a lot of side effects for an individual -and- has success -- don't forget, placebo effects, as you note can have up to 30% results. Some people are suggestible and if given hard candy in a pill will respond. This is no criticism of them, this is just how their brain operates.
But as I noted, if an agent even works for 30% of people for a particular disorder one can say that one is doing quite well considering chemotherapy agents can have as little as 10% improvement rates and are given when the benefits (extended life, time to be with the world and those that they love) outweigh the risks.
Posted by Neal on February 28, 2008, at 14:55:56
In reply to Re: ADs found to offer little clinical benefit » Netch, posted by yxibow on February 28, 2008, at 8:08:39
these kinds of studies have been around for years. And you can bet that someone brings them breathlessly to the board each time.
I have found usefulness in some drugs from personal experience and that is all I need to know.
Neal
Posted by Larry Hoover on March 1, 2008, at 13:34:54
In reply to ADs found to offer little clinical benefit, posted by Netch on February 26, 2008, at 4:48:17
> http://www.news-medical.net/?id=35583
>
> /NetchI don't know why you didn't post the whole article, including this: "Professor Kirsch says patients should not change their treatment without speaking to their doctor, but said other approaches such as physical exercise, psychoanalysis and self-help books, have been found to help."
Right. Kirsch is a psychologist. Hardly biased. Note how he totally ignores the additive effect of medication and psychotherapy, which have vastly superior response and remission rates than do either modality alone.
Kirsch studied the identical dataset, in 2002 (Prevention: "The Emperor's New Drugs: An Analysis of Antidepressant Medication Data Submitted to the U.S. Food and Drug Administration"). His "findings" then were no different than now. How could they be? It's the same (incomplete) data! And the criticisms and limitations of his work have not changed, either. At least, he then had the sense to express doubt about antidepressant clinical trial methodology, when he said: "If there is a powerful antidepressant effect, then it is being masked by a nonadditive placebo effect, in which case current clinical trial methodology may be inappropriate for evaluating these medications, and alternate methodology need to be developed." He was absolutely correct to raise this question. Returning to the old dataset, without addressing this issue further, only makes him a hyprocrite, IMHO.
I have profound contempt for this latest work.
I can think of no valid reason to restrict the meta-analysis to research of such great age (11 to 20 years old), other than that the "results" were already known. There is a vast body of more competent, more recent, more extensive, and more relevant research which was totally ignored. The only redeeming feature is that at least he came up with the same statistics that he derived nearly six years before. However, his statistics have no external validity then, nor now.
External validity involves the generalizability of the findings of the study, outwards from the small sample of subjects studied, to the general population. For any antidepressant clinical trial (or collections of clinical trials, as in this meta-analysis) to have external validity, then a number of characteristics must be true. Just two of these assumptions are that the subjects taking part in the study are typical of the population to which the findings are to be generalized, and that these subjects are treated in ways typical to treatment in the real world. Well, let's take a look at these factors.
Are the participants typical? No! It has been estimated that less than 1 in 10 of all persons who present in a doctor's office with symptoms of depression would be eligible to participate in an antidepressant clinical trial. Some estimates go to as few as 1 in 30 eligible participants. Usually, exclusions are due to concurrent illness (having more than one medical issue), and/or concurrent medication, or history of other illness. So, right away, we've lost external validity between clinical trials, and clinical practise. Most of us aren't like these people at all. But there's far more to consider.
Participants in clinical trials are self-selected. They consent; they're not compelled. I have never seen anyone try to determine what psychological variables self-selection bias might bring to a clinical trial. Were they motivated by free medication? Payment for participation? Why wouldn't they be concerned about the 50% possibility of getting an inactive medication, if they are truly as depressed as they say they are? I have other subject-related concerns, but I'll move on to methodology.
Are real people treated the way they are in a clinical trial? Again, no! No, they are not. How do you think the researchers obtain their Hamilton Depression scores, or their own subjective measures of antidepressant response? By paying attention to their subjects, frequently and extensively. I've taken part in a clinical trial (not antidepressant), and let me tell you, I can only wish for that level of supportive attention. I have a gem of a doctor, and I'm not putting him down to say he can't come close. Is it any surprise that depressed people might respond to intensive attention and concern? A little loving?
Another huge issue: the duration of the trials. Some were of only four weeks' duration. How does that compare with standard clinical practise? Even at six weeks, or eight weeks (the greatest duration in this dataset), are we to assume that all possible response had already occurred? All we know is that they stopped measuring response at those points in time.
Remember, Kirsch himself questioned the methodology. And I'm going to demonstrate why I think his just-published study verifies his 2002 thesis that this older methodology obscures the true drug response with placebo artefact. The word artefact arises from the same root meaning as artificial. Antidepresant clinical trials are wholly artificial environments, and we must be very careful in reaching conclusions from the data so obtained, most particularly conclusions about external validity.
Let's take a look at the recent Kirsch paper. It's here: http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pmed.0050045
The entire paper is really heavy on the statistics, and I don't presume to understand all the niceties myself, even though I consider myself to be well-versed on stats. However, you don't need to be a statistician to grasp the issues I intend to bring out.
One of the first is this quotation, from the Results section: "...the mean change (in Hamilton Depression Scale scores) exhibited in trials provides a poor description of results..." Problem #1: All his conclusions are based on analyses of mean change. If the data are poor, so are the stats derived from them. Garbage in, garbage out.
He uses some fancy statistical methods to derive standardized and normalized values for the mean differences in Hamilton score. Whenever standardization or normalization are done, the effect is to reduce variability. In other words, the differences get smaller. That's a pretty good trick. Nonetheless, in every model he employed, antidepressants were found to be superior to placebo, p <0.001. (See Table 2: http://medicine.plosjournals.org/perlserv/?request=slideshow&type=table&doi=10.1371/journal.pmed.0050045&id=13865 ) That is statistical significance, but he wants to use what he calls clinical significance. More on that in a minute.
He makes numerous references to NICE (National Institute for Clinical Excellence) Guideline 23, entitled "Depression: Management of depression in primary and secondary care". I had to look it up, as I'd never heard of it before. An excellent meta-analysis of depression treatments, by the way. http://www.nice.org.uk/guidance/index.jsp?action=download&o=29617
One of the reasons I was delayed in my response to this thread is that the NICE document is rather large, at 363 pages. Anyway, it is the source of the term "clinical significance", which Kirsch uses as his threshold of efficacy. I needed to know what he was talking about, before I could properly criticize his work.
The simplest way to summarize the meaning is to say that it represents the magnitude of difference in response between drug and placebo in a clinical trial that would show unequivocal benefit in clinical practise (i.e. the real world). Just for the record, NICE did the same sort of analyses on the same dataset as did Kirsch, and here's what they found:
p.168
There is strong evidence suggesting that there is a clinically significant difference favouring SSRIs over placebo on increasing the likelihood of patients achieving a 50% reduction in depression symptoms as measured by the HRSD (N = 1719; n = 3143; RR = 0.73; 95% CI, 0.69 to 0.78).THERE IS A CLINICALLY SIGNIFICANT DIFFERENCE FAVOURING SSRIs OVER PLACEBO, IF REMISSION IS THE CRITERION.
I can only believe Kirsch already was aware of this finding. However, he works with a different analysis of clinical significance, employing the Hamilton scale in a way he's already described as a poor descriptor of results. NICE already did that analysis, too, and they said:
p.169
There is evidence suggesting that there is a statistically significant difference favouring SSRIs over placebo on reducing depression symptoms as measured by the HRSD but the size of this difference is unlikely to be of clinical significance (N = 16; n = 2223; Random effects SMD = 0.34; 95% CI, 0.47 to 0.22).KIRSCH ALREADY KNEW THE ANSWER. IT REALLY IS NOTHING NEW.
My own interpretation is that the randomness in the data obscures the ability to measure a true difference between the two groups, but only when analyzed in this particular way. Talk about cherry-picking.
Now, Kirsch did produce some nice graphs, and I don't think you need any background in stats to understand them. I strongly recommend that you take a look at them.
Consider Figure 3: http://medicine.plosjournals.org/perlserv/?request=slideshow&type=figure&doi=10.1371/journal.pmed.0050045&id=96827
Here, Kirsch presents the highly manipulated (standardized) difference score, d, as a function of depression severity. These are severely depressed subjects. Just from a quick look, would you rather be in the triangle group (drug), or the circles (placebo)? I pick triangle.
Notice also that the average drug effect line is horizontal. What I see is that this is the true drug effect, writ large. It is obscured by the placebo effect, which falls off when depression severity makes it less likely to occur. The placebo effect obscures the drug effect, just as Kirsch himself postulated in 2002.
Now, here's a very illustrative figure, Figure 4: http://medicine.plosjournals.org/perlserv/?request=slideshow&type=figure&doi=10.1371/journal.pmed.0050045&id=96831
First, the zero line is no difference (i.e. superiority) of drug or placebo. Below zero is placebo superiority, whereas above it is drug superiority. What's the pattern tell you? Do we find just as many points below the zero line, and just as far from it, as we do above it?
Second, Kirsch calculated an average difference between drug and placebo of 1.8, favouring drugs. Take a piece of paper, and cover that part of the graph above 1.8 (just over half way between zero and that green line at 3). Then, do the same, but cover all points below 1.8. Does the pattern look the same? Does it appear to you that 1.8 *is* the average value? Not even close, in my estimation. His derived statistic is not representative of the data points. The reason is that he normalized it (manipulated it) first.
The *only* evidence that Kirsch supplied that suggest that this ancient clinical trial data is generalizable to the population at large (i.e. that it has external validity) is that NICE came up with a statistic that might be used to do so. I don't believe that Kirsch met his burden.
I could continue to flog this horse.....For example, we know that placebo responders are far more likely to relapse, and to do so far sooner than do those continuing with antidepressant treatment. And I reiterate, Kirsch doesn't even mention the large superiority in response and remission seen with combined antidepressant and psychotherapy.
I think the lay press ought to get a smack upside the head for buying this recycled line without critical analysis, too. But that's another story.
Lar
Posted by chumbawumba on May 11, 2009, at 19:33:27
In reply to Re: ADs.......offer MUCH clinical benefit!!!!!!!!!, posted by Jay_Bravest_Face on February 27, 2008, at 5:01:00
> Well, my take and experience (15 years or so) is that over time and with experiments, YES, medications CAN and DO work.
>
> When I first started on meds, a tiny dose of a Elavil and Ativan was tossed at me, and of course it did very little. Then the SSRIs where big, and I tried, and they did a little bit more, but not much. Then the SNRIs, first generation like Effexor, and did more, but still not enough. Then many combos, with my bipolar diagnosis, and mood stabilizers, and still no go. And, modern day, we are working with a new generation SNRI, Cymbalta, and a dash of older Prozac, plus Risperdal for mood stabilization and Topamax as well..oh and clonazepam, and I have really been seem to be doing fine.Actually I think your experience supports the results of the study, antidepressants BY THEMSELVES seem to do very little. (I'm not sure if I buy the results of the study, but your experience actually supports rather than refutes it) You've got Cymbalta, Prozac, Risperdal, Topamax, and Clonazepam on board. You're not exactly a poster child for the benefits of monotherapy.
But I'm glad you're better. Sorry it took a while.
Posted by chumbawumba on May 11, 2009, at 20:00:49
In reply to Re: ADs.......offer MUCH clinical benefit!!!!!!!!!, posted by Jay_Bravest_Face on February 27, 2008, at 5:01:00
> Well, my take and experience (15 years or so) is that over time and with experiments, YES, medications CAN and DO work.
>
> When I first started on meds, a tiny dose of a Elavil and Ativan was tossed at me, and of course it did very little. Then the SSRIs where big, and I tried, and they did a little bit more, but not much. Then the SNRIs, first generation like Effexor, and did more, but still not enough. Then many combos, with my bipolar diagnosis, and mood stabilizers, and still no go. And, modern day, we are working with a new generation SNRI, Cymbalta, and a dash of older Prozac, plus Risperdal for mood stabilization and Topamax as well..oh and clonazepam, and I have really been seem to be doing fine.
>Actually your experience supports the results of the study. You tried an antidepressant and it did not work for you. It took the two antidepressants, plus Risperdal, Topamax, and Clonazepam for you to get relief.
This is the end of the thread.
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