![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 29 to 53 of 53. Go back in thread:
Posted by SLS on October 22, 2013, at 6:34:23
In reply to Re: Irving Kirsch, placebos and antidepressants, posted by linkadge on October 19, 2013, at 17:16:23
> Dopamine increases the motivation to act. Serotonin (ie. SSRIs) counteracts this. SSRIS decrease the motivation and drive to act or achieve things.
Is this true of SSRIs even when they produce a robust antidepressant response, or is this associated only with non-response? I don't doubt that SSRI-induced apathy and amotivation are acute effects, but what happens after receptor desensitization occurs? Wouldn't these unwanted effects dissipate?
I don't know, of course.
- Scott
Posted by SLS on October 22, 2013, at 6:38:25
In reply to Re: Irving Kirsch, placebos and antidepressants » Phillipa, posted by doxogenic boy on October 19, 2013, at 7:02:52
> I found this diagnosis in DSM-5:
> "Persistent complex bereavement disorder: This disorder is characterized by severe and persistent grief and mourning reactions"
>
> Do they prescribe antidepressants for this in America?I believe so. Columbia / New York State Psychiatric Institute has been studying this for at least a year.
- Scott
Posted by doxogenic boy on October 22, 2013, at 8:36:39
In reply to Re: Irving Kirsch, placebos and antidepressants » doxogenic boy, posted by SLS on October 22, 2013, at 6:38:25
> > I found this diagnosis in DSM-5:
> > "Persistent complex bereavement disorder: This disorder is characterized by severe and persistent grief and mourning reactions"
> >
> > Do they prescribe antidepressants for this in America?
>
> I believe so. Columbia / New York State Psychiatric Institute has been studying this for at least a year.Have they found evidence that antidepressants work for this diagnosis? Are the patients satisfied?
- doxogenic
Posted by doxogenic boy on October 22, 2013, at 8:45:25
In reply to Re: Irving Kirsch, placebos and antidepressants » linkadge, posted by SLS on October 22, 2013, at 6:34:23
> > Dopamine increases the motivation to act. Serotonin (ie. SSRIs) counteracts this. SSRIS decrease the motivation and drive to act or achieve things.
>
> Is this true of SSRIs even when they produce a robust antidepressant response, or is this associated only with non-response? I don't doubt that SSRI-induced apathy and amotivation are acute effects, but what happens after receptor desensitization occurs? Wouldn't these unwanted effects dissipate?
--Isn't SSRI-induced apathy a long-term side effect of SSRIs?
See this study:
http://www.ncbi.nlm.nih.gov/pubmed/12019662
Excerpt from the abstract above:
J Clin Psychiatry. 2002 May;63(5):391-5.
Olanzapine in the treatment of apathy in previously depressed participants maintained with selective serotonin reuptake inhibitors: an open-label, flexible-dose study.
Marangell LB, Johnson CR, Kertz B, Zboyan HA, Martinez JM.
SourceMood Disorders Center, Department of Psychiatry, Baylor College of Medicine, Houston, Tex 77030, USA. laurenm@bcm.tmc.edu
Abstract
BACKGROUND:We report a clinical trial of olanzapine in the treatment of prominent apathy in the absence of depression in patients on long-term treatment with selective serotonin reuptake inhibitors (SSRIs) for nonpsychotic major depression.
[...]
CONCLUSION:These preliminary data suggest that olanzapine may be effective in treating apathy syndrome in nonpsychotic patients taking SSRIs.
End quote.Do you know of patients with SSRI-induced apathy that have been helped with atypical antipsychotics?
- doxogenic
Posted by SLS on October 22, 2013, at 11:30:29
In reply to Re: Irving Kirsch, placebos and antidepressants » SLS, posted by doxogenic boy on October 22, 2013, at 8:45:25
This is good. Thanks.
Lauren Marangell is a respectable academician.
- Scott> > > Dopamine increases the motivation to act. Serotonin (ie. SSRIs) counteracts this. SSRIS decrease the motivation and drive to act or achieve things.
> >
> > Is this true of SSRIs even when they produce a robust antidepressant response, or is this associated only with non-response? I don't doubt that SSRI-induced apathy and amotivation are acute effects, but what happens after receptor desensitization occurs? Wouldn't these unwanted effects dissipate?
> --
>
> Isn't SSRI-induced apathy a long-term side effect of SSRIs?
>
> See this study:
> http://www.ncbi.nlm.nih.gov/pubmed/12019662
> Excerpt from the abstract above:
> J Clin Psychiatry. 2002 May;63(5):391-5.
> Olanzapine in the treatment of apathy in previously depressed participants maintained with selective serotonin reuptake inhibitors: an open-label, flexible-dose study.
> Marangell LB, Johnson CR, Kertz B, Zboyan HA, Martinez JM.
> Source
>
> Mood Disorders Center, Department of Psychiatry, Baylor College of Medicine, Houston, Tex 77030, USA. laurenm@bcm.tmc.edu
> Abstract
> BACKGROUND:
>
> We report a clinical trial of olanzapine in the treatment of prominent apathy in the absence of depression in patients on long-term treatment with selective serotonin reuptake inhibitors (SSRIs) for nonpsychotic major depression.
> [...]
> CONCLUSION:
>
> These preliminary data suggest that olanzapine may be effective in treating apathy syndrome in nonpsychotic patients taking SSRIs.
> End quote.
>
> Do you know of patients with SSRI-induced apathy that have been helped with atypical antipsychotics?
>
> - doxogenic
Posted by doxogenic boy on October 22, 2013, at 11:46:43
In reply to Re: Irving Kirsch, placebos and antidepressants » doxogenic boy, posted by SLS on October 22, 2013, at 11:30:29
Thanks for your reply.
Here is a case report which indicates that dose reduction can help for SSRI-induced apathy.
http://www.ncbi.nlm.nih.gov/pubmed/21240154
Psychopharmacol Bull. 2010;43(4):76-9.
Antidepressant induced apathy responsive to dose reduction.
Kodela S, Venkata PD.
SourceCarilion Clinic-Virginia Tech Psychiatry Residency Program, Roanoke, VA, USA. sreekant.kodela@googlemail.com
AbstractApathy has a significant negative impact on the quality of life. It can be a part of other axis I and axis III disorders such as depression. It has also been reported as a treatment emergent side effect of SSRI drugs. A 48 year old male with diagnosis of personality change due to medical condition and depressive symptoms was started on Sertraline. Although his depressive symptoms, impulse control and his irritability improved significantly he became quite apathetic. This responded positively to a reduction in the dose of sertraline. Since apathy can be a residual symptom of depression it may be a valid consideration to increase the dose of the SSRI. However if apathy was not a significant part of depressive syndrome prior to SSRI treatment then antidepressant treatment emergent apathy needs to be considered and one option is to reduce the dose of the SSRI. Other options appear to be addition of other pharmacological agents such as stimulants, dopamine agonists, acetylcholinesterase inhibitors and NMDA antagonists.
- doxogenic
Posted by babbler20 on October 30, 2013, at 21:57:56
In reply to Re: Irving Kirsch, placebos and antidepressants » Phillipa, posted by doxogenic boy on October 18, 2013, at 11:03:52
> > Same thing my pdoc said that even in his opinion that ad's are more of a placebo effect. That life circumstances play more a role. Also the hope of the patient that "well now I have a med I am better".
>
> Could you ask your pdoc what he thinks about Irving Kirsch's claims about antidepressants and placebo, as mentioned is this thread? Do the mental health professionals in the United States discuss this topic a lot? I am very curious about what psychiatrists say about this.
>
> The placebo effect is part of the effect of every treatment for any disease. (I have never heard of a treatment that does not have a placebo effect in addition to the pharmacological effect.)
>
> I have read earlier in Scientific American Mind that the reason for the high placebo responses in drug studies for antidepressants in the United States, is that some of/lots of patients in the studies weren't depressed in the first place. (I think they got money for participating in the studies.) Therefore the placebo response looks higher than it is. What do you think about this?
>
> - doxogenicDoxogenic,
I actually hadn't considered the fact that many of the patients that were given the placebo weren't depressed. This is an excellent point !
Posted by doxogenic boy on November 2, 2013, at 9:14:04
In reply to Re: Irving Kirsch, placebos and antidepressants, posted by babbler20 on October 30, 2013, at 21:57:56
> > I have read earlier in Scientific American Mind that the reason for the high placebo responses in drug studies for antidepressants in the United States, is that some of/lots of patients in the studies weren't depressed in the first place. (I think they got money for participating in the studies.) Therefore the placebo response looks higher than it is. What do you think about this?
> Doxogenic,
>
> I actually hadn't considered the fact that many of the patients that were given the placebo weren't depressed. This is an excellent point !Yes, I think the pharmaceutical companies will take this into consideration in future trials/research, because they obviously lose money when they get too high placebo responses. So maybe the Kirsch/placebo debate took place on false premises?
Here is an overview of that debate:
http://web.archive.org/web/19990128083252/http://journals.apa.org/prevention/
http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.0050045
http://ebmh.bmj.com/content/11/3/66.full
- doxogenic
Posted by larryhoover on November 2, 2013, at 22:23:38
In reply to Irving Kirsch, placebos and antidepressants, posted by doxogenic boy on October 18, 2013, at 8:23:17
Kirsch is a man who selects his data to match his hypothesis, manipulating the data until the stats say what he wishes them to say, IMHO.
It was a while ago, when I wrote this, but I haven't changed my mind.
http://www.dr-bob.org/babble/20080221/msgs/815551.html
Lar
Posted by rockerchick46 on November 3, 2013, at 1:52:39
In reply to Re: Irving Kirsch, placebos and antidepressants » doxogenic boy, posted by larryhoover on November 2, 2013, at 22:23:38
Hi Larry.
Thank you.
- Scott
Posted by rockerchick46 on November 3, 2013, at 6:56:16
In reply to Re: Irving Kirsch, placebos and antidepressants » larryhoover, posted by rockerchick46 on November 3, 2013, at 1:52:39
> Hi Larry.
>
> Thank you.
>
>
> - ScottI'm defintely not Scott :-)
Posted by doxogenic boy on November 4, 2013, at 12:26:10
In reply to Re: Irving Kirsch, placebos and antidepressants » doxogenic boy, posted by larryhoover on November 2, 2013, at 22:23:38
> Kirsch is a man who selects his data to match his hypothesis, manipulating the data until the stats say what he wishes them to say, IMHO.
>
> It was a while ago, when I wrote this, but I haven't changed my mind.
>
> http://www.dr-bob.org/babble/20080221/msgs/815551.htmlI have read your message from 2008 with interest. I am no expert, so I can't contradict any of your findings. Do you know of more articles (from psychologist or psychiatrists) with critical analyses of Kirsch's claims about antidepressants? My interest into this is because of a general interest in psychiatry and because I use psychotropic drugs myself.
- doxogenic
Posted by larryhoover on November 4, 2013, at 22:55:52
In reply to Re: Irving Kirsch, placebos and antidepressants » larryhoover, posted by doxogenic boy on November 4, 2013, at 12:26:10
> Do you know of more articles (from psychologist or psychiatrists) with critical analyses of Kirsch's claims about antidepressants? My interest into this is because of a general interest in psychiatry and because I use psychotropic drugs myself.
>
> - doxogenicYou'll also find links to some very cogent critical reviews of Kirsch referenced within this article.
Here's a much more useful analysis of similar data reported upon by Kirsch:
http://www.nice.org.uk/nicemedia/pdf/cg023fullguideline.pdfA re-analysis of Kirsch's data, showing he misreported his results:
http://www.ncbi.nlm.nih.gov/pubmed/20800012Lar
Posted by doxogenic boy on November 6, 2013, at 17:57:31
In reply to Re: Irving Kirsch, placebos and antidepressants » doxogenic boy, posted by larryhoover on November 4, 2013, at 22:55:52
> > Do you know of more articles (from psychologist or psychiatrists) with critical analyses of Kirsch's claims about antidepressants? My interest into this is because of a general interest in psychiatry and because I use psychotropic drugs myself.
> >
> > - doxogenic
>
> You'll also find links to some very cogent critical reviews of Kirsch referenced within this article.
>
> http://blogs.plos.org/mindthebrain/2012/12/26/the-antidepressant-wars-a-sequel-how-the-media-distort-findings-and-do-harm-to-patients/
>
> Here's a much more useful analysis of similar data reported upon by Kirsch:
> http://www.nice.org.uk/nicemedia/pdf/cg023fullguideline.pdf
>
> A re-analysis of Kirsch's data, showing he misreported his results:
> http://www.ncbi.nlm.nih.gov/pubmed/20800012
Thank you very much, this was new information for me. I have found some more:http://www.ncbi.nlm.nih.gov/pubmed/19588448
Quote from the link above:
Cochrane Database Syst Rev. 2009 Jul 8;(3):CD007954. doi: 10.1002/14651858.CD007954.
Antidepressants versus placebo for depression in primary care.
Arroll B, Elley CR, Fishman T, Goodyear-Smith FA, Kenealy T, Blashki G, Kerse N, Macgillivray S.
SourceDepartment of General Practice and Primary Health Care, University of Auckland, Private Bag 92019, Auckland, New Zealand.
Abstract
BACKGROUND:Concern has been expressed about the relevance of secondary care studies to primary care patients specifically about the effectiveness of antidepressant medication. There is a need to review the evidence of only those studies that have been conducted comparing antidepressant efficacy with placebo in primary care-based samples.
OBJECTIVES:To determine the efficacy and tolerability of antidepressants in patients (under the age of 65 years) with depression in primary care.
SEARCH STRATEGY:All searches were conducted in September 2007.The Cochrane Depression, Anxiety and Neurosis Group (CCDAN) Controlled Trials Register was searched, together with a supplementary search of MEDLINE, PsycINFO, EMBASE, LILACS, CINAHL and PSYNDEX. Abstracts of all possible studies for inclusion were assessed independently by two reviewers. Further trials were sought through searching the reference lists of studies initially identified and by scrutinising other relevant review papers. Selected authors and experts were also contacted.
SELECTION CRITERIA:Studies were selected if they were randomised controlled trials of tricyclic antidepressants (TCAs) or selective serotonin reuptake inhibitors (SSRIs) versus placebo in adults. Older patients (over 65 years) were excluded. Patients had to be recruited from a primary care setting. For continuous outcomes the Hamilton Depression scale of the Montgomery Asberg Scale was requred.
DATA COLLECTION AND ANALYSIS:Data were extracted using data extraction forms by two reviewers independently, with disagreements resolved by discussion. A similar process was used for the validity assessment. Pooling of results was done using Review Manager 5. The primary outcome was depression reduction, based on a dichotomous measure of clinical response, using relative risk (RR), and on a continuous measure of depression symptoms, using the mean difference (MD), with 95% confidence intervals (CI).
MAIN RESULTS:There were fourteen studies (16 comparisons) with extractable data included in the review, of which ten studies examined TCAs, two examined SSRIs and two included both classes, all compared with placebo. The number of participants in the intervention groups was 1364 and in the placebo groups 919. Nearly all studies were of short duration, typically 6-8 weeks. Pooled estimates of efficacy data showed an RR of 1.24, 95% CI 1.11-1.38 in favour of TCAs against placebo. For SSRIs this was 1.28, 95% CI 1.15 to 1.43.. The numbers needed to treat (NNT) for TCAs ranged from 7 to 16 {median NNT 9} patient expected event rate ranged from 63% to 26% respectively) and for SSRIs from 7 to 8 {median NNT 7} (patient expected event rate ranged from 48% to 42% respectively) . The numbers needed to harm (NNH for withdrawal due to side effects) ranged from 4 to 30 for TCAs (excluding three studies with no harmful events leading to withdrawal) and 20 to 90 for SSRIs.
AUTHORS' CONCLUSIONS:Both TCAs and SSRIs are effective for depression treated in primary care.
End quote.
----------------------------
http://www.ncbi.nlm.nih.gov/pubmed/22033583Quote from the link above:
Eur Arch Psychiatry Clin Neurosci. 2011 Nov;261 Suppl 3:207-45. doi: 10.1007/s00406-011-0259-6.
General and comparative efficacy and effectiveness of antidepressants in the acute treatment of depressive disorders: a report by the WPA section of pharmacopsychiatry.
Baghai TC, Blier P, Baldwin DS, Bauer M, Goodwin GM, Fountoulakis KN, Kasper S, Leonard BE, Malt UF, Stein D, Versiani M, Möller HJ; Section of Pharmacopsychiatry, World Psychiatric Association.
Collaborators (46)
SourceDepartment of Psychiatry and Psychotherapy, Ludwig-Maximilian-University of Munich, Nussbaumstrasse 7, 80336, Munich, Germany. Thomas.Baghai@medbo.de
AbstractCurrent gold standard approaches to the treatment of depression include pharmacotherapeutic and psychotherapeutic interventions with social support. Due to current controversies concerning the efficacy of antidepressants in randomized controlled trials, the generalizability of study findings to wider clinical practice and the increasing importance of socioeconomic considerations, it seems timely to address the uncertainty of concerned patients and relatives, and their treating psychiatrists and general practitioners. We therefore discuss both the efficacy and clinical effectiveness of antidepressants in the treatment of depressive disorders. We explain and clarify useful measures for assessing clinically meaningful antidepressant treatment effects and the types of studies that are useful for addressing uncertainties. This includes considerations of methodological issues in randomized controlled studies, meta-analyses, and effectiveness studies. Furthermore, we summarize the differential efficacy and effectiveness of antidepressants with distinct pharmacodynamic properties, and differences between studies using antidepressants and/or psychotherapy. We also address the differential effectiveness of antidepressant drugs with differing modes of action and in varying subtypes of depressive disorder. After highlighting the clinical usefulness of treatment algorithms and the divergent biological, psychological, and clinical efforts to predict the effectiveness of antidepressant treatments, we conclude that the spectrum of different antidepressant treatments has broadened over the last few decades. The efficacy and clinical effectiveness of antidepressants is statistically significant, clinically relevant, and proven repeatedly. Further optimization of treatment can be helped by clearly structured treatment algorithms and the implementation of psychotherapeutic interventions. Modern individualized antidepressant treatment is in most cases a well-tolerated and efficacious approach to minimize the negative impact of otherwise potentially devastating and life-threatening outcomes in depressive disorders.
End quote.
-----------------------------------
http://www.ncbi.nlm.nih.gov/pubmed/23552610
Quote from the link above:Psychol Med. 2013 Apr 3:1-11. [Epub ahead of print]
Comparison of psychotherapies for adult depression to pill placebo control groups: a meta-analysis.
Cuijpers P, Turner EH, Mohr DC, Hofmann SG, Andersson G, Berking M, Coyne J.
SourceDepartment of Clinical Psychology, VU University Amsterdam, The Netherlands.
Abstract
BACKGROUND:The effects of antidepressants for treating depressive disorders have been overestimated because of selective publication of positive trials. Reanalyses that include unpublished trials have yielded reduced effect sizes. This in turn has led to claims that antidepressants have clinically insignificant advantages over placebo and that psychotherapy is therefore a better alternative. To test this, we conducted a meta-analysis of studies comparing psychotherapy with pill placebo. Method Ten 10 studies comparing psychotherapies with pill placebo were identified. In total, 1240 patients were included in these studies. For each study, Hedges' g was calculated. Characteristics of the studies were extracted for subgroup and meta-regression analyses.
RESULTS:The effect of psychotherapy compared to pill placebo at post-test was g = 0.25 [95% confidence interval (CI) 0.14-0.36, I 2 = 0%, 95% CI 0-58]. This effect size corresponds to a number needed to treat (NNT) of 7.14 (95% CI 5.00-12.82). The psychotherapy conditions scored 2.66 points lower on the Hamilton Depression Rating Scale (HAMD) than the placebo conditions, and 3.20 points lower on the Beck Depression Inventory (BDI). Some indications for publication bias were found (two missing studies). We found no significant differences between subgroups of the studies and in meta-regression analyses we found no significant association between baseline severity and effect size.
CONCLUSIONS:Although there are differences between the role of placebo in psychotherapy and pharmacotherapy research, psychotherapy has an effect size that is comparable to that of antidepressant medications. Whether these effects should be deemed clinically relevant remains open to debate.
End quote.- doxogenic
Posted by larryhoover on November 9, 2013, at 12:50:16
In reply to Re: Irving Kirsch, placebos and antidepressants » larryhoover, posted by doxogenic boy on November 6, 2013, at 17:57:31
Darn, I feel an essay coming on.
First, I'd like to examine the measurement of depression severity in clinical trials. The most commonly employed is the Hamilton Depression scale, symbolized as the HAM-D, or HRSD.
It's administered in an interview format, where the interviewer asks the subject to assess their symptoms in seventeen different variables. A numerical value is assigned to each response, and the sum of the values is the HAM-D score.
http://healthnet.umassmed.edu/mhealth/HAMD.pdfThe result is always an integer. You might have a 14 or a 15, but never a 14.5. But what exactly does that number represent? Although it's used to approximate the severity of an individual's depression, are two people with equal scores equally depressed? And if they both change by two points, have they improved or declined by equal amounts? The fact is, we have no way of knowing the answer to those questions.
That's because the results of the HAM-D are ordinal data. We can rank the scores of individual results, but that's about all we can say.
I'll give you another example of ordinal data, the results of a marathon race. We can award first, second, third places, and so on, but we cannot determine what the time differential might have been between these ranked results. Only other measures can provide that insight.
The problem for psychology/psychiatry is that there is no other measure available to us, to assess the validity of what we've measured. We may employ other ordinal scales, such as the Montgomery-Åsberg Depression Rating Scale (MADRS), or the Beck Depression Inventory (BDI) (there are many others out there, but these are the most common alternatives to HAM-D), but we still can't get around the fact that there is no external validation for any of them.
One of the desired outcomes of any double-blind clinical trial is to provide evidence for the effect of an active treatment (such as a drug) when compared to a placebo treatment. The problem is that ordinal data only permit the most basic of summary statistics.
From a position of statistical rigor, you're only permitted to determine the median value (the value right in the middle of the ranked measurements, e.g the 50th value in a list of 100), and the mode value (the one most frequently measured). The only permitted graphical representation of the data is a histogram (bar graph, or frequency line plot).
You're not allowed to calculate means, standard deviations, confidence intervals, statistical significance.....and yet, every clinical trial does exactly that. It's kind of like a gentlemen's agreement, "We've got to try and pull something meaningful out of these data, and we'll use these summary statistics to do it, even though we probably shouldn't."
For more on the types of data, and the permitted statistics, here's a nice summary on wiki: http://en.wikipedia.org/wiki/Level_of_measurement
Probably the most meaningful of a derived statistic for a clinical trial is an individual's difference score, i.e. the change in HAM-D score between the time a subject began the clinical trial, and its completion. I'll get to other concerns about confounding variables later, but at least the same subject is being compared to himself, over time.
I want to talk about what Kirsch did, now. Here's a link to the PLOS article he wrote: http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0050045
I will quote from his work, which will always appear in quotation marks. Everything else is my commentary. One of the big issues for me is methodology. If you don't assess how the author(s) define their approach, you can't properly assess the results. Here we go:
Kirsch used only drug pre-approval data, in the period from 1987 and 1999. He remarks, "This strategy omits trials conducted after approval was granted." Why would he want to do that, as his stated premise was to determine 'clinical efficacy', which is more or less defined as results expected in the general population?
"In addition, the FDA independently reviews the clinical trial methods, statistical procedures, and results. The FDA dataset includes analyses of data from all patients who attended at least one evaluation visit, even if they subsequently dropped out of the trial prematurely. Results are reported from all well-controlled efficacy trials of the use of these medications for the treatment of depression. FDA medical and statistical reviewers had access to the raw data and evaluated the trials independently." I'm at a loss here. Is he impugning the FDA? I'll come back to this point later.
"The use of other psychoactive medication was reported in 25 trials" Out of a total of 47, by the way. So, for more than half of the data, placebo participants may have been exposed to active medication, after all. Despite this obvious potential confound, it does not enter into any of his statistical analyses, and I don't recall it ever being mentioned again.
The next concept under consideration involves standardization. You have to do that when different measurements are used in different studies. I don't know all of the parameters that Kirsch standardized, but he certainly collapsed 4,5,6 and 8 week study durations together, collapsed across patient groups (inpatient, outpatient, elderly), and probably the HAM-D scores themselves (Hamilton himself has published 5 versions of his 17-question test, while others have modified it to include up to 29 questions). In any case, when you standardize data, you reduce the variability. It's inherent in what you're doing, as you're doing nothing more than deciding to ignore some differences in the data. And yet, Kirsch assumes that standardization had no effect on the variability.
The capital S in the next quote represents 'Standardized'.
"In total, SDcs were known for 28 groups, could be calculated from other inferential statistics in nine comparisons (18 groups), and were imputed in 12 comparisons (24 groups) (47.38%) [13,14]." It's further described in the actual article, but when he says "imputed", what he means is he made up the data. He declares quite plainly that if data were "outliers" (not clustered with the others), he treated them as if they were missing data, and he made up values for those deleted ones. I don't know where you stand on this, but deleting data and making up data are both problems for me.
This next one simply makes me wonder. It's not about Kirsch, per se. But look at the difference in group sizes. "The dataset comprised 35 clinical trials (five of fluoxetine, six of venlafaxine, eight of nefazodone, and 16 of paroxetine) involving 5,133 patients, 3,292 of whom had been randomized to medication and 1,841 of whom had been randomized to placebo."
But no matter what he did with the data, his main outcome measures, presented in Table 2, were that drug was significantly superior to placebo, p <.001. All the rest of the paper is an attempt to provide an intellectual construct which dismisses his own statistical results, IMHO.
Kirsch applied statistical measures which were completely inappropriate, based on ordinal data, but his own evidence was that drugs were significantly better than placebo. His conclusions are not supported by the data.
We do not know that, as an example, the difference between a HAM-D score of 14 and 15, is the same magnitude as the difference between 24 and 25. We do not know that the subjects were assessed under identical circumstances (even time of day could make a difference). We do no know that expectancy played no part in the measures. What if some patients (placebo or drug) reported improvements because they didn't want to disappoint the doctor running the trial?
To do what Kirsch did here was completely inappropriate. He didn't even reference similar work undertaken by other researchers. Kirsch is neither the first, nor the only person, to attempt to interpret the clinical trial data on antidepressants collectively. A balanced report would certainly have included references to others raising similar questions.
One such researcher is Arif Khan. I like this quote from Dr. Khan, from the April 2000 volume of Psychiatric Times:
"The less-than-impressive results in these and other studies also calls to mind the fact that patients assigned to placebo treatment in clinical trials are not "getting nothing." The capsule they receive is pharmacologically inert but hardly inert with respect to its symbolic value and its power as a conditioned stimulus. In addition, placebo-treated patients receive all of the commonly employed treatment techniques: a thorough evaluation; an explanation for their distress; an expert healer; a plausible treatment; expectation of improvement; a healer's commitment, enthusiasm and positive regard; and an opportunity to verbalize their distress. Jerome Frank, Ph.D., in his book Persuasion and Healing: A Comparative Study of Psychotherapy made a compelling case that these parts of treatment are the active ingredients of all the psychotherapies (1993)....
A cautionary note is indicated about the generalization of these data to the clinical management of depressed patients. The less-than-impressive difference between drug and placebo in this and other studies of clinical trials does not speak directly to the effectiveness of antidepressants in clinical practice. Participants in antidepressant clinical trials are a highly select group and are not representative of the general population of depressed patients. They are not actively suicidal, they are almost always outpatients who are moderately rather than severely or mildly depressed, and they are free of comorbid physical or psychiatric illness. They are likely to have a higher placebo response rate than more severely ill depressed patients.
Furthermore, the primary aim of these studies is not to assess the optimal effect of antidepressants, but rather to rapidly assess efficacy of new drugs so they can be brought to the market. Therefore, dose, duration and diagnosis in clinical trials are not necessarily ideally suited to identify the optimal effects of antidepressants. Accordingly, clinical trials may identify the lower bound of the effect size compared to placebo."
My conclusion is that Kirsch's work is unreliable and unscientific. In totality, I believe that Kirsch simply used this paper to express his personal beliefs, in the guise of scientific inquiry. It was intellectually dishonest, misleading, and ultimately, disgraceful.
Now, I'm going to step aside from Kirsch, and speak of my own experience. I have participated in a clinical trial. I have helped design a clinical trial (based on my experience). And I have read numerous clinical trial submissions to the regulators (which include all raw data, often measuring over 300 pages).
I only wish that real life medical practise even fractionally approximated the level of care that goes into a clinical trial. My own physicians gave me great care during my difficult times, but that care never came close to the degree of personal interaction that is required to gather the data for a clinical trial. Comparing double-blind efficacy trial environments to those experienced by patients in real life is simply inappropriate.....and yet we do so, unthinkingly.
I would suggest that less than 10% of depressed patients would even qualify for a clinical trial. The exclusion criteria are quite comprehensive, because they must define the study population precisely, if there is to be any hope that the measurements are valid. Most of us don't fit nicely into those intellectual cubby holes.
And I suspect that the population here also is unrepresentative of the general population. This is a self-selected population of people questioning, struggling, seeking to expand the scope of their existing care.
I mentioned a moment ago that I have read the raw data for some clinical trials. It truly is remarkable just how much information is collected. And how often it is misinterpreted, based on summary statistics.
It's been a while since I wrote about it, but in this link you'll see a lengthy post by me that also has a couple of tinyurl hyperlinks. Lots of info in those.
http://www.dr-bob.org/cgi-bin/pb/mget.pl?post=/babble/20050504/msgs/494929.html
Posted by larryhoover on November 9, 2013, at 12:54:01
In reply to Re: Irving Kirsch, placebos and antidepressants » doxogenic boy, posted by larryhoover on November 9, 2013, at 12:50:16
Posted by doxogenic boy on November 11, 2013, at 12:06:25
In reply to Re: Irving Kirsch, placebos and antidepressants » doxogenic boy, posted by larryhoover on November 9, 2013, at 12:50:16
Thank you very much for your thoughts about this. I have now read your three posts from alt.support.depression.medication too. I used to read that newsgroups about ten years ago, but last time I checked, it was dead.
I have found a meta analysis in fulltext in Canadian Medical Association Journal:
http://www.cmaj.ca/content/178/3/296.long
Excerpt from article:
Effectiveness of paroxetine in the treatment of acute major depression in adults: a systematic re-examination of published and unpublished data from randomized trialsCorrado Barbui MD,
Toshiaki A. Furukawa MD,
Andrea Cipriani MD[...]
Interpretation: Among adults with moderate to severe major depression in the clinical trials we reviewed, paroxetine was not superior to placebo in terms of overall treatment effectiveness and acceptability. These results were not biased by selective inclusion of published studies.
End quote.
------------------------
Have you seen this article before, and what do you think about it?I found the meta analysis in the references list of this article:
http://tidsskriftet.no/article/3001711/en_GB
I have met O.B. Fasmer (one of the authors) once as a patient.- doxogenic
Posted by doxogenic boy on November 11, 2013, at 13:06:44
In reply to Re: Irving Kirsch, placebos and antidepressants » larryhoover, posted by doxogenic boy on November 11, 2013, at 12:06:25
>I have now read your three posts from alt.support.depression.medication too. I used to read that newsgroups about ten years ago, but last time I checked, it was dead.
Correction to my statement above: "I used to read that newsgroup ..." (without "s".)
> I found the meta analysis in the references list of this article:
> http://tidsskriftet.no/article/3001711/en_GB
> I have met O.B. Fasmer (one of the authors) once as a patient.Clarification: I was Fasmer's patient, but only one appointment, for evaluation purposes only.
- doxogenic
Posted by larryhoover on December 6, 2013, at 22:27:45
In reply to Re: Irving Kirsch, placebos and antidepressants » larryhoover, posted by doxogenic boy on November 11, 2013, at 12:06:25
> I have found a meta analysis in fulltext in Canadian Medical Association Journal:
>
> http://www.cmaj.ca/content/178/3/296.long
>
> Excerpt from article:
> Effectiveness of paroxetine in the treatment of acute major depression in adults: a systematic re-examination of published and unpublished data from randomized trials
>
> Corrado Barbui MD,
> Toshiaki A. Furukawa MD,
> Andrea Cipriani MD
>
> [...]
> Interpretation: Among adults with moderate to severe major depression in the clinical trials we reviewed, paroxetine was not superior to placebo in terms of overall treatment effectiveness and acceptability. These results were not biased by selective inclusion of published studies.I had not seen this article before, and frankly I don't know whether to laugh or to cry.
They have decided that the the primary criterion for antidepressant efficacy is not the actual change in depression score (which actually significantly lies with antidepressant treatment), and instead substitute their own measure, drop-out rate.
In the abstract, they clarify that significantly more subjects dropped out in the treatment arm because of side effects (paxil is notorious for side effects), but they fail to account for the fact that the net drop-out rate was equivalent between the groups (RR = 0.99), yet they don't account for what might have balanced the two groups overall (e.g. lack of efficacy in the placebo group, perhaps?).
I've been kind, so far, to consider the report on face value, so far. But have you ever seen an antidepressant rated by its drop-out rate against placebo? Do you think that the medical regulators would accept this as a criterion of efficacy? Do you think that scientific studies should be re-assessed on parameters that were not primary controlled measures of the methodology? No, No, and No.
This is a garbage article. I am aghast.
Lar
Posted by doxogenic boy on December 7, 2013, at 5:26:34
In reply to Re: Irving Kirsch, placebos and antidepressants » doxogenic boy, posted by larryhoover on December 6, 2013, at 22:27:45
>
> > I have found a meta analysis in fulltext in Canadian Medical Association Journal:
> >
> > http://www.cmaj.ca/content/178/3/296.long
> >
> > Excerpt from article:
> > Effectiveness of paroxetine in the treatment of acute major depression in adults: a systematic re-examination of published and unpublished data from randomized trials
> >
> > Corrado Barbui MD,
> > Toshiaki A. Furukawa MD,
> > Andrea Cipriani MD
> >
> > [...]
> > Interpretation: Among adults with moderate to severe major depression in the clinical trials we reviewed, paroxetine was not superior to placebo in terms of overall treatment effectiveness and acceptability. These results were not biased by selective inclusion of published studies.
>
> I had not seen this article before, and frankly I don't know whether to laugh or to cry.
>
> They have decided that the the primary criterion for antidepressant efficacy is not the actual change in depression score (which actually significantly lies with antidepressant treatment), and instead substitute their own measure, drop-out rate.
>
> In the abstract, they clarify that significantly more subjects dropped out in the treatment arm because of side effects (paxil is notorious for side effects), but they fail to account for the fact that the net drop-out rate was equivalent between the groups (RR = 0.99), yet they don't account for what might have balanced the two groups overall (e.g. lack of efficacy in the placebo group, perhaps?).
>
> I've been kind, so far, to consider the report on face value, so far. But have you ever seen an antidepressant rated by its drop-out rate against placebo? Do you think that the medical regulators would accept this as a criterion of efficacy? Do you think that scientific studies should be re-assessed on parameters that were not primary controlled measures of the methodology? No, No, and No.
>
> This is a garbage article. I am aghast.Thank you for your response. I am relieved by your evaluation of this article, because I am satisfied with my medication (see this post: http://www.dr-bob.org/babble/20130828/msgs/1050311.html ) and it would be really disappointing if antidepressants were just placebo.
Since I use agomelatine, I don't like the conclusion of this article:
http://bjp.rcpsych.org/content/203/3/179.abstract?sid=b54ffe6b-dfcb-4716-ac8a-ef15b6a36a38"We found evidence suggesting that a clinically important difference between agomelatine and placebo in patients with unipolar major depression is unlikely. There was evidence of substantial publication bias."
Unfortunately, I don't have access to it in full text, but do you think it is likely that their claims are correct? Then it indicates that Servier has fooled the medical authorities in several countries.
Here is a full text article:
http://bjp.rcpsych.org/content/195/3/211.long"Emotional side-effects of selective serotonin reuptake inhibitors: qualitative study"
They used this method:
"Qualitative study, gathering data through individual interviews, a group interview and validation interviews; and searching patient websites for relevant posts."Is this a reliable method for this purpose?
- doxogenic
Posted by larryhoover on December 7, 2013, at 11:51:13
In reply to Re: Irving Kirsch, placebos and antidepressants » larryhoover, posted by doxogenic boy on December 7, 2013, at 5:26:34
> Since I use agomelatine, I don't like the conclusion of this article:
> http://bjp.rcpsych.org/content/203/3/179.abstract?sid=b54ffe6b-dfcb-4716-ac8a-ef15b6a36a38
>
> "We found evidence suggesting that a clinically important difference between agomelatine and placebo in patients with unipolar major depression is unlikely. There was evidence of substantial publication bias."The evidence that they found, and what they conclude about it, are different things.
In the Results section: "Acute treatment with agomelatine was associated with a statistically significant superiority over placebo..."
End of story.
A clinical trial environment is not comparable to real-life treatment. I had a very caring and supportive family physician, who referred me to a very caring and supportive psychiatrist for expert care, but neither one came close to the level of support I received when I participated in a clinical trial. The clinical trial environment exaggerates placebo response, because a lot more goes on besides simply taking a sugar pill.
Here are a couple of earlier threads on that subject. The second one directly addresses the issues I've raised.
http://www.dr-bob.org/babble/20070911/msgs/782723.html
http://www.dr-bob.org/babble/20090104/msgs/873232.html
> Unfortunately, I don't have access to it in full text, but do you think it is likely that their claims are correct? Then it indicates that Servier has fooled the medical authorities in several countries.
Their conclusion is based on a construct of psychological care, which is really a philosophical point, rather than a medical one.
The idea of a "clinically important difference" is not testable. In essence, these authors are giving an opinion, that on a cost/benefit, risk/reward impression, they don't believe that this particular drug is worth using. Even though they confirmed that the drug treatment is better than placebo treatment, including unpublished evidence.
> Here is a full text article:
> http://bjp.rcpsych.org/content/195/3/211.long
>
> "Emotional side-effects of selective serotonin reuptake inhibitors: qualitative study"
>
> They used this method:
> "Qualitative study, gathering data through individual interviews, a group interview and validation interviews; and searching patient websites for relevant posts."
>
> Is this a reliable method for this purpose?
>
> - doxogenicSure, it's an acceptable exercise, but it doesn't really provide anything new. There's no testable hypothesis coming out of it. Some people don't tolerate the effects of their antidepressants, and some of that intolerance has emotional roots.
I had good antidepressant effects on some drugs, but in each successful instance, I also became impotent. That was a deal-breaker for me.
To continue on a drug, or not, is a matter between the patient and his physician.
There are many treatment modalities that don't involve drugs. Drugs are not the solution for everyone. But that does not mean that drug treatment should be withheld, based on a biased reinterpretation of clinical trial data. The clinical trials were never meant to be a representation of real-life treatment.
I have never yet seen one of these critical reviews of clinical trial data that failed to find that drug treatment was significantly superior to placebo. And yet, somehow they come up with rhetoric to suggest that there is no difference. That's politics, not science.
Lar
Posted by SLS on December 7, 2013, at 15:43:15
In reply to Re: Irving Kirsch, placebos and antidepressants » doxogenic boy, posted by larryhoover on December 7, 2013, at 11:51:13
> I have never yet seen one of these critical reviews of clinical trial data that failed to find that drug treatment was significantly superior to placebo. And yet, somehow they come up with rhetoric to suggest that there is no difference. That's politics, not science.
Yup.
- Scott
Posted by ed_uk2010 on December 8, 2013, at 1:26:24
In reply to Re: Irving Kirsch, placebos and antidepressants » larryhoover, posted by SLS on December 7, 2013, at 15:43:15
Part of the problem with psych drugs (as you well know), is that not only can they make people feel a lot better, they (including exactly the same drug) can make other people feel a lot worse. In any large trial, the overall response rate is confused and muddied by the large variability in response between different pts. The overall response rate to one specific drug therefore tends to end up looking unimpressive. Of course, this is hardly the only problem with trialing psych drugs, just one of many.
Posted by ed_uk2010 on December 8, 2013, at 1:31:34
In reply to Re: Irving Kirsch, placebos and antidepressants » doxogenic boy, posted by larryhoover on December 7, 2013, at 11:51:13
>I had good antidepressant effects on some drugs, but in each successful instance, I also became impotent. That was a deal-breaker for me.
Sildenafil is now so cheap over here you can get a prescription (eg. TEVA, Actavis, Sandoz, not Pfizer's Viagra) for about the price of a bottle of shampoo. Not sure about North America. Have no idea about the current relevance of this information to your health, but thought it was worth a post!
Posted by doxogenic boy on December 8, 2013, at 13:35:38
In reply to Re: Irving Kirsch, placebos and antidepressants » doxogenic boy, posted by larryhoover on December 7, 2013, at 11:51:13
Thank you very much for the response.
- doxogenic
This is the end of the thread.
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