{"id":27263,"date":"2012-09-13T01:21:18","date_gmt":"2012-09-13T05:21:18","guid":{"rendered":"http:\/\/1boringoldman.com\/?p=27263"},"modified":"2012-09-13T07:43:16","modified_gmt":"2012-09-13T11:43:16","slug":"eyes-wide-shut-open-iii","status":"publish","type":"post","link":"https:\/\/1boringoldman.com\/index.php\/2012\/09\/13\/eyes-wide-shut-open-iii\/","title":{"rendered":"eyes wide <strike>shut<\/strike> open III\u2026"},"content":{"rendered":"\n<div align=\"justify\">Change of plans. In the last episode&#8230; [as they said in the serials at the Saturday movies when I was a kid in the 40&#8217;s], I said I was going to show real raw data, then an example of how the summary data like in <strong><font color=\"#200020\">ClinicalTrials.gov <\/font><\/strong>might miss something important. I was going to use the GSK computer printouts from Study 329 [<a href=\"http:\/\/1boringoldman.com\/index.php\/2012\/08\/24\/the-lesson-of-study-329-the-basics\/\"><strong><u><font color=\"#200020\">the lesson of Study 329: the basics&hellip;<\/font><\/u><\/strong><\/a>] for the raw data example, and the summary data from Lilly&#8217;s Study LYAQ, that wasn&#8217;t enough to really vet the Robert Gibbons et al Meta-Analysis of pediatric suicidality on antidepressants [<strong><a href=\"http:\/\/1boringoldman.com\/index.php\/2012\/03\/06\/come-rest-a-while-ii\/\" target=\"_blank\"><u><font color=\"#200020\">come rest a while II&hellip;<\/font><\/u><\/a><\/strong>].<\/div>\n<ul>\n<div align=\"justify\"><em>That was way, way too complicated. The short version is, &quot;I found a better example.&quot; I&#8217;m starting over.<br \/>            <\/em><\/div>\n<\/ul>\n<div align=\"justify\">In case I haven&#8217;t said it directly, I hate it when people cheat by manipulating data. So I&#8217;m always redrawing graphs to start at zero, and trying to show the primary data rather than derived values. It was a lesson learned from good teachers a long time ago, and it&#8217;s still a fine one. So from 1997, here&#8217;s the very first study of Prozac in adolescents:            <\/div>\n<blockquote>\n<div align=\"center\"><u><strong><font color=\"#200020\">A Double-blind, Randomized, Placebo-Controlled Trial of Fluoxetine in Children and Adolescents With Depression<\/font><\/strong><\/u><br \/>                            <sup>by  Graham J. Emslie, MD; A. John Rush, MD; Warren A. Weinberg, MD; Robert  A. Kowatch, MD; Carroll W. Hughes, PhD; Tom Carmody, PhD; and Jeanne  Rintelmann<\/sup><br \/>                            <strong><font color=\"#200020\">Archives of General Psychiatry<\/font><\/strong>. 1997, 54:1031-1037. <\/div>\n<p>            <\/p>\n<div align=\"justify\"><sup><u>Background<\/u>: Depression is a  major cause of morbidity and mortality in children and adolescents. To  date, randomized, controlled, double-blind trials of antidepressants  (largely tricyclic agents) have yet to reveal that any antidepressant is  more effective than placebo. This article is of a randomized,  double-blind, placebo controlled trial of fluoxetine in children and  adolescents with depression.<br \/>                            <u>Method<\/u>:  Ninety-six child and adolescent outpatients (aged 7-17 years) with  nonpsychotic major depressive disorder were randomized (stratified for  age and sex) to 20 mg of fluoxetine or placebo and seen weekly for 8  consecutive weeks. Randomization was preceded by 3 evaluation visits  that included structured diagnostic interviews during 2 weeks, followed 1  week later by a 1-week, single-blind placebo run-in. Primary outcome  measurements were the global improvement of the Clinical Global  Impressions scale and the Children&rsquo;s Depression Rating Scale &ndash; Revised, a  measure of the severity depressive symptoms.<br \/>                            <u>Results<\/u>:  Of the 96 patients, 48 were randomized to fluoxetine treatment and 48  to placebo. Using the intent to treat sample, 27 (56%) of those  receiving fluoxetine and 16 (33%) receiving placebo were rated &quot;much&quot; or  &quot;very much&quot; improved on the Clinical Global Impressions scale at study  exit (chi 2=5.1, df=1, P=.02). Significant differences were also noted  in weekly ratings of the Children&rsquo;s Depression Rating Scale &ndash; Revised  after 5 weeks of treatment (using last observation carried forward).  Equivalent response rates were found for patients aged 12 years and  younger (n=48) and those aged 13 years and older (n=48). However,  complete symptom remission (Children&rsquo;s Depression Rating Scale &ndash;  Revised) occurred in only 31% of the fluoxetine-treated patients and 23%  of the placebo patients.<br \/>                            <u>Conclusion<\/u>: Fluoxetine  was superior to placebo in the acute phase treatment of major  depressive disorder in child and adolescent outpatients with severe,  persistent depression. Complete remission of symptoms was rare.<\/sup><\/div>\n<div align=\"center\"><img decoding=\"async\" width=\"390\" vspace=\"5\" border=\"0\" src=\"http:\/\/1boringoldman.com\/images\/proz-2.gif\" \/><\/div>\n<\/blockquote>\n<div align=\"justify\">      I had redrawn and colored the graph for clarity back when I originally looked at this study <a href=\"http:\/\/1boringoldman.com\/index.php\/2011\/07\/22\/tuning-the-quartet\/\" target=\"_blank\"><u><strong><font color=\"#200020\">last July<\/font><\/strong><\/u><\/a>, but omitted the legend. Here&#8217;s the graph and the explanatory text from the full-text paper. Notice the <em>(last observation carried forward)<\/em> in the figure&#8217;s legend:     <\/div>\n<blockquote>\n<div align=\"center\"><img loading=\"lazy\" decoding=\"async\" width=\"300\" vspace=\"5\" height=\"263\" border=\"0\" src=\"http:\/\/1boringoldman.com\/images\/x065-1.gif\" \/><\/div>\n<div align=\"justify\"><sup>The other primary outcome measure, the weekly CDRS-R score, was examined as a continuous variable. Figure 2 shows the traditional method of dealing with patient attrition during the course of the treatment [ie, weekly CDRS-R scores for each group are presented with the LOCF]. The last available observation is filled in for the values for patients who discontinued study participation before 8 weeks&#8230; Comparing the weekly CDRS-R scores for each treatment group using t tests, the first week that the groups were significantly different was week 5. At week 5, the mean CDRS-R score for the fluoxetine-treated group [39.8&plusmn;13.2] was lower than the placebo group [46.8&plusmn;16.6] [t=-2.28, df=94, P=.03]. To make the most efficient use of the available data without resorting to a completion analysis or LOCF analysis, the rate of change [slope] and baseline CDRS-R score [intercept]) were estimated from linear regressions on each patient and for each group. The estimated baselines were similar [54.2 for the fluoxetine-treated group vs 53.8 for the placebo group]. However, the fluoxetine-treated group slope of -2.75&plusmn;-2.52 was significantly different from the placebo group slope of -1.27&plusmn;-2.86 [t=2.68, df=94, P&lt;.001]. <\/p>\n<p>     These results may be interpreted as follows. The fluoxetine-treated group began with an average CDRS-R score of 54.2 and their scores improved by 2.75 U per week to end with an estimated week 8 score of 32.2. While placebo patients began with a similar average CDRS-R score [53.8], their score improved only 1.27 U per week to the end of the study with an estimated exit score of 43.6. Using the empirical Bayesian analysis of estimating slopes [intercept estimates were unavailable] gives an estimated slope of -2.60&plusmn;2.36 for the fluoxetine treated group and a significantly smaller slope of -1.32&plusmn;3.56 for the placebo group [t=2.08, df=94,P=.04].<\/sup><\/div>\n<\/blockquote>\n<div align=\"justify\">Since I looked at that study last July, I was trying to vet the very suspicious study of Gibbons et al claiming that SSRIs were both safe and effective in adolescents based on a meta-analysis of the old Prozac studies, and I discovered that Lilly had posted a version of their data on a <a href=\"http:\/\/www.lillytrials.com\/\" target=\"_blank\"><u><strong><font color=\"#200020\">Clinical Trials site<\/font><\/strong><\/u><\/a>. It&#8217;s not the raw data [by subject]. It&#8217;s summary tables. I looked at it to find out about study LYAQ, but I&#8217;d never looked at study X065 &#8211; that&#8217;s the one discussed above. As I scanned through it, I ran across<strong><a href=\"http:\/\/www.lillytrials.com\/results\/prozac.pdf#page=32\" target=\"_blank\"><u><font color=\"#200020\"> this graph<\/font><\/u><\/a><\/strong>:     <\/div>\n<div align=\"center\"><a target=\"_blank\" href=\"http:\/\/www.lillytrials.com\/results\/prozac.pdf#page=32\"><img loading=\"lazy\" decoding=\"async\" width=\"450\" vspace=\"7\" height=\"655\" border=\"0\" src=\"http:\/\/1boringoldman.com\/images\/x065.gif\" \/><\/a><\/div>\n<div align=\"justify\">First off, it doesn&#8217;t look like the published version. That&#8217;s because it&#8217;s the raw data instead of being corrected using the last observation carried forward. And the bottom version is what happens when you convert it to <em>change in score<\/em> from the raw data.<\/div>\n<p align=\"justify\">Study X065 was the first Clinical Trial of an SSRI [Prozac] in Adolescents. <strong><font color=\"#200020\">It was one of the two studies used by Lilly to get approval for Prozac in the treatment of MDD in Adolescents [the only SSRI approved for kids since it got through the FDA before the black box warning was imposed].<\/font><\/strong> To my knowledge, the only sight we have of the primary raw data from this study is the top graph in Figure X065.2 above. The published graph [LOCF] and the % change lower graph are ways to make things look better on paper. And the verbiage in the article [quoted above] is an indirect way of claiming a difference using regression slopes, in lieu of showing us that simple raw data graph [which clearly shows no difference].   <\/p>\n<p align=\"justify\">So that&#8217;s why I want the <strong><font color=\"#200020\">raw data<\/font><\/strong>. If I had seen that top X065.2 graph, I would&#8217;ve simply said, Prozac doesn&#8217;t help depressed kids, no matter what the manipulated versions showed. So would you. That&#8217;s why they didn&#8217;t show it. There&#8217;s a second point. <a target=\"_blank\" href=\"http:\/\/1boringoldman.com\/index.php\/2012\/03\/06\/come-rest-a-while-i\/\"><u><strong><font color=\"#200020\">Gibbons et al<\/font><\/strong><\/u><\/a> used this data in his meta-analysis that said the SSRIs were efficacious in adolescents. All I see is even more evidence that his meta-analysis is flawed&#8230;<\/p>\n<div align=\"center\"><img decoding=\"async\" border=\"0\" src=\"http:\/\/1boringoldman.com\/images\/x065-2.gif\" \/><br \/> <sup>[what they saw] &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp;&nbsp; &nbsp; &nbsp; <\/sup><sup> &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp;&nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp;&nbsp; [what we saw]<\/sup><\/div>\n","protected":false},"excerpt":{"rendered":"<p>Change of plans. In the last episode&#8230; [as they said in the serials at the Saturday movies when I was a kid in the 40&#8217;s], I said I was going to show real raw data, then an example of how the summary data like in ClinicalTrials.gov might miss something important. I was going to use [&hellip;]<\/p>\n","protected":false},"author":2,"featured_media":0,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_bbp_topic_count":0,"_bbp_reply_count":0,"_bbp_total_topic_count":0,"_bbp_total_reply_count":0,"_bbp_voice_count":0,"_bbp_anonymous_reply_count":0,"_bbp_topic_count_hidden":0,"_bbp_reply_count_hidden":0,"_bbp_forum_subforum_count":0,"footnotes":""},"categories":[2],"tags":[],"class_list":["post-27263","post","type-post","status-publish","format-standard","hentry","category-politics"],"_links":{"self":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/27263","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/comments?post=27263"}],"version-history":[{"count":26,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/27263\/revisions"}],"predecessor-version":[{"id":27289,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/27263\/revisions\/27289"}],"wp:attachment":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/media?parent=27263"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/categories?post=27263"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/tags?post=27263"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}