{"id":54185,"date":"2015-02-14T08:00:52","date_gmt":"2015-02-14T13:00:52","guid":{"rendered":"http:\/\/1boringoldman.com\/?p=54185"},"modified":"2015-02-14T21:12:19","modified_gmt":"2015-02-15T02:12:19","slug":"a-cul-de-sac-i","status":"publish","type":"post","link":"https:\/\/1boringoldman.com\/index.php\/2015\/02\/14\/a-cul-de-sac-i\/","title":{"rendered":"a cul de sac I&#8230;"},"content":{"rendered":"<br \/>\n<blockquote>\n<div align=\"center\" class=\"big\"><a href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/25586212\" target=\"_blank\">The International Study to Predict Optimized Treatment in Depression [iSPOT-D]: Outcomes from the acute phase of antidepressant treatment<\/a><\/div>\n<div align=\"center\" class=\"small\">by Saveanu R, Etkin A, Duchemin AM, Goldstein-Piekarski A, Gyurak A, Debattista C, Schatzberg AF, Sood S, Day CV, Palmer DM, Rekshan WR, Gordon E, Rush AJ, Williams LM.<\/div>\n<div align=\"center\" class=\"middle\"><strong><font color=\"#200020\">Journal of Psychiatric Research<\/font><\/strong>. 2015 61:1-12.                   <\/div>\n<p align=\"justify\">We aimed to characterize a large international cohort of outpatients with MDD within a practical trial design, in order to identify clinically useful predictors of outcomes with three common antidepressant    medications in acute-phase treatment of major depressive disorder (MDD). The international Study to    Predict Optimized Treatment in Depression has presently enrolled 1008 treatment-seeking outpatients [18 &#8211; 65 years old] at 17 sites [five countries]. At pre-treatment, we characterized participants by    symptoms, clinical history, functional status and comorbidity. Participants were randomized to receive    escitalopram, sertraline or venlafaxine-extended release and managed by their physician following usual    treatment practices. Symptoms, function, quality of life, and side-effect outcomes were assessed 8 weeks    later. The relationship of anxiety to response and remission was assessed by comorbid Axis I diagnosis,    presence\/absence of anxiety symptoms, and dimensionally by anxiety symptom severity. The sample had    moderate-to-severe symptoms, but substantial comorbidity and functional impairment. Of completers at    week 8, 62.2% responded and 45.4% reached remission on the 17-item Hamilton Rating Scale for    Depression; 53.3% and 37.6%, respectively on the 16-item Quick Inventory of Depressive Symptoms.    Functional improvements were seen across all domains. Most participants had side effects that occurred    with a frequency of 25% or less and were reported as being in the &ldquo;none&rdquo; to minimal\/mild range for    intensity and burden.<\/p>\n<div align=\"justify\">Outcomes did not differ across medication groups. More severe anxiety symptoms at pre-treatment were associated with lower remission rates across all medications, independent of depressive severity, diagnostic comorbidity or side effects. Across medications, we found consistent and similar improvements in symptoms and function, and a dimensional prognostic effect of comorbid anxiety symptoms. These equivalent outcomes across treatments lay the foundation for identifying potential neurobiological and genetic predictors of treatment outcome in this sample.<\/div>\n<\/blockquote>\n<div align=\"justify\" class=\"small\">The third paragraph of the paper says:                       <\/div>\n<ul>\n<div align=\"justify\" class=\"small\"><em><u><strong><font color=\"#990000\">Recent efforts<\/font><\/strong><\/u><font color=\"#300030\"> <\/font>have focused on identifying clinical or laboratory-based measures that help to precisely target treatments for specific patients. While several neurobiological markers have been investigated, none have been of sufficient clinical value to be incorporated into treatment guideline recommendations&hellip;.<\/em><\/div>\n<\/ul>\n<p align=\"justify\" class=\"small\">That paragraph deserves a little more introduction: <\/p>\n<table cellspacing=\"0\" cellpadding=\"2\" border=\"0\" width=\"98%\" align=\"center\">\n<tr>\n<td align=\"center\"> <strong><font color=\"#200020\">BACKGROUND<\/font><\/strong>        <\/p>\n<hr size=\"1\" \/><\/td>\n<\/tr>\n<tr>\n<td>\n<div align=\"justify\" class=\"small\">As the decade following the coming of Prozac drew to a close, it was apparent that the new antidepressants were no panacea for symptomatic depression &#8211; at least not being prescribed in the chaotic way they were being used. Some thought that we should give the medication in a systematic way, with guidelines, with objective measurement data. This thread is about the <u><em><strong><font color=\"#990000\">some<\/font><\/strong><\/em><\/u> that thought that was the problem. We needed alogorithms for our treatment. Who know the right way to sive these medications? The Experts [the <u><em><strong><font color=\"#990000\">some<\/font><\/strong><\/em><\/u>] &#8211; that&#8217;s who. So we&#8217;ll create algorithms for the drugs used to treat Schizophrenia, Bipolar Disorder, Major Depressive Disorder [MDD], by Expert Consensus for our clinicians to follow as a guide to treatment. And where shall we do this, in the largest public mental health system there is &#8211; The State of Texas. Thus, in 1996, the Texas Medical Algorithm Project [<a href=\"http:\/\/1boringoldman.com\/index.php\/2011\/05\/28\/algorithmic-psychiatry-the-early-days\/\" target=\"_blank\">TMAP<\/a>] came into existence &#8211; generously supported by Foundations, the State of Texas, and multiple pharmaceutical companies, all coordinated by the psychiatrists of the University of Texas system. The algorithms spread to multiple States, and the Federal Government when the Texas Governor became the US President.                    <\/div>\n<p align=\"justify\" class=\"small\">The idea of applying systematic study using clinical&nbsp; trials of these algorithms appealed to the NIMH, and there followed a period of large acronymed Clinical Trials in Depression, Schizophrenia, Bipolar Disorder, and other disorders.. The largest, <a href=\"http:\/\/1boringoldman.com\/index.php\/2011\/04\/03\/a-thirty-five-million-dollar-misunderstanding\/\" target=\"_blank\">STAR*D<\/a> [<font color=\"#200020\"><span class=\"st\">Sequenced Treatment Alternatives to Relieve Depression<\/span><\/font>], was run by the <font color=\"#200020\">TMAP<\/font> team and had a complex, sequential algorithm in which non-responders were changed to another drug or <em>augmentation <\/em>scheme. In MDD, there was a side project, <font color=\"#200020\">IMPACTS<\/font> [<a href=\"http:\/\/1boringoldman.com\/index.php\/2011\/05\/28\/algorithmic-psychiatry-fallacy\/\" target=\"_blank\">algorithmic psychiatry: the fallacy&hellip;<\/a>] that computerized&nbsp; the algorithms. It had to be scrapped because the clinicians wouldn&#8217;t use it if left to their own devices. Then came <a href=\"http:\/\/1boringoldman.com\/index.php\/2013\/03\/27\/an-outrageous-waste\/\" target=\"_blank\">COMED<\/a> which combined multiple antidepressants &#8211; no help. I think it&#8217;s reasonable for me to say that all of these efforts generated much ado and many papers, spent tons of money, but not much changed in the response rates of MDD to antidepressants [if you&#8217;re not up to speed, just look up any acronym using the  search box at the bottom of this page]:                   <\/p>\n<p align=\"center\"><img decoding=\"async\" border=\"0\" width=\"450\" src=\"http:\/\/1boringoldman.com\/images\/prefer.gif\" \/><\/p>\n<p align=\"justify\" class=\"small\">That pretty much covers the completed <u><em><strong><font color=\"#990000\">efforts<\/font><\/strong><\/em><\/u> in <u><em><strong><font color=\"#990000\">Recent efforts<\/font><\/strong><\/em><\/u>. Now for the <u><em><strong><font color=\"#990000\">Recent<\/font><\/strong><\/em><\/u> part. Since all of this started, there have been some new kids on the block. Genomics, Proteinomics, Functional Neoroimaging, Cognitive Testing. <em>Well, not new kids, but at least more prominent shiny new objects in neuroscience. <\/em>And in the rest of medicine, <a href=\"http:\/\/1boringoldman.com\/index.php\/2011\/04\/18\/personalized-medicine-the-concept\/\" target=\"_blank\"><font color=\"#200020\">Personalized Medicine<\/font><\/a> [picking specific treatment based on unique biomarkers], had become a hot new area. <em>Well, not a new area, but at least more prominent shiny new object in neuroscience.<\/em> So <font color=\"#200020\">Personalized Medicine<\/font> began to be bandied about as a possible exploratory area for picking an antidepressant &#8211; the scientific rationale being <em><font color=\"#200020\">&laquo;fill in the blank?&raquo;<\/font><\/em>. And a new character entered the ring &#8211; Evian Gordon, a brain training Australian [<a href=\"http:\/\/1boringoldman.com\/index.php\/2011\/04\/19\/personalized-medicine-brainnet\/\" target=\"_blank\">BrainNet<\/a>] &#8211; and his colleague, Leanne Williams [<a href=\"http:\/\/1boringoldman.com\/index.php\/2011\/04\/19\/personalized-medicine-the-brain-resources-company\/\" target=\"_blank\">Brain Resources<\/a>]. They gathered a <a href=\"http:\/\/1boringoldman.com\/index.php\/7604-2\/\" target=\"_blank\">who&#8217;s who of KOLs<\/a> [list] for their <font color=\"#200020\">Personalized Medicine Action Group<\/font> in D.C. in October 2009 to kick off a campaign to personalize antidepressant treatment [<strong><a target=\"_blank\" href=\"http:\/\/brainnet.net\/media\/video_action.php?playfor=brainnet&#038;iframe=true&#038;width=770&#038;height=480\"><font color=\"#660033\">The Mayflower<\/font><\/a><\/strong>] [which is a must-see to understand this line of thinking].                <\/p>\n<div align=\"justify\" class=\"small\">In the year before this conference [2008], Senator Grassley&#8217;s congressional investigation had reshuffled the people he exposed who had unreported PHARMA income. John Rush [of <font color=\"#200020\">TMAP, STAR*D,<\/font> and<font color=\"#200020\"> CO-MED<\/font>] left UT and went to Duke in Singapore. Alan Shatzberg, APA President, stepped down as Chairman at Stanford. Charlie Nemeroff, Boss of Bosses, was removed at Emory and went to Miami as chair. The emptiness of the PHARMA new drugs <em>pipeline<\/em> was looming. Out of that matrix, two large Personalized Medicine studies came into being. <font color=\"#200020\">iSpot-D<\/font> was financed by Evian Gordon&#8217;s BrainNet\/BrainResources [see <a target=\"_blank\" href=\"http:\/\/1boringoldman.com\/index.php\/2011\/04\/20\/personalized-medicine-the-brain-resources-company-ii\/\">personalized medicine: the Brain Resources company II&hellip;<\/a>] and added the Grassley-investigated people to his byline&#8230;            <\/div>\n<blockquote>\n<div align=\"center\" class=\"big\"><a target=\"_blank\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC3036635\/\">International    Study to Predict Optimized Treatment for Depression [iSPOT-D], a    randomized clinical trial: rationale and protocol.<\/a><\/div>\n<div align=\"center\" class=\"small\">by Williams LM, <strong><font color=\"#990000\">Rush AJ<\/font><\/strong>, Koslow SH,  Wisniewski SR, Cooper NJ, <strong><font color=\"#990000\">Nemeroff CB<\/font><\/strong>, <strong><font color=\"#990000\">Schatzberg AF<\/font><\/strong>, Gordon E.<\/div>\n<div align=\"center\" class=\"middle\"><strong>Trials<\/strong>. 2011 12:4.<\/div>\n<div align=\"center\" class=\"middle\">[<a href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC3036635\/\" target=\"_blank\">full text online<\/a>]<\/div>\n<\/blockquote>\n<div align=\"justify\" class=\"small\">Meanwhile, Dr. Madhukar Trivedi, still at UT Southwestern, started a second Personalized Medicine study, <strong><font color=\"#200020\">EMBARC<\/font><\/strong> [<a target=\"_blank\" href=\"http:\/\/www.depressioncenter.org\/research\/participate\/embarc\/\">Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care<\/a>], with a large <strong><font color=\"#200020\">NIMH<\/font><\/strong> grant, mentioning many of the STAR*D veterans as resources in his grant proposals [see <a href=\"http:\/\/1boringoldman.com\/index.php\/2011\/05\/04\/8463\/\" target=\"_blank\">the race for biomarkers&hellip;<\/a> and <a href=\"http:\/\/1boringoldman.com\/index.php\/2011\/05\/05\/godzilla-vs-ghidorah-the-three-headed-monster-from-outer-space\/\" target=\"_blank\">Godzilla vs. Ghidorah&#8230;<\/a>]. This second Clinical Trial is still <em>recruiting<\/em>.           <\/div>\n<\/td>\n<\/tr>\n<tr>\n<td align=\"center\">\n<hr size=\"1\" \/><strong><font color=\"#200020\">SCIENCE<\/font><\/strong>        <\/p>\n<hr size=\"1\" \/><\/td>\n<\/tr>\n<tr>\n<td>\n<div align=\"justify\" class=\"small\">The scientific premise behind this line of thinking and series of trials was questionable from the outset. The notion that Major Depressive Disorder as defined represents a distinct clinical entity, a unitary disease entity, was conjecture that has now rapidly moved to the realm of fantasy. The evidence for an over-riding biological etiology was equally scant, and has traveled in the same direction. Likewise, by any ongoing reading of the accumulating information, the therapeutic action of the <em>antidepressant drugs<\/em> is a non-specific, symptomatic effect &#8211; not something determined by the kind of precise or controllable biological mechanisms hypothesized in these studies &#8211; certainly nothing tied to etiology.<\/div>\n<\/td>\n<\/tr>\n<tr>\n<td align=\"center\">\n<hr size=\"1\" \/><strong><font color=\"#200020\">COMMERCE<\/font><\/strong>        <\/p>\n<hr size=\"1\" \/><\/td>\n<\/tr>\n<tr>\n<td>\n<div align=\"justify\" class=\"small\">The entrepreneurial background in this story should really be  considered more a part of the foreground. <font color=\"#200020\">TMAP<\/font> was exposed by  whistle-blower Allen Jones to be a conduit for PHARMA to introduce  in-patent drugs to the public sector without evidence of efficacy  justifying their use, facilitated by under-the-counter payoffs to  officials. <font color=\"#200020\">TMAP<\/font> was shut down and the States have tried to retrieve  their considerable losses with varying levels of success. To be fair,  the payola was between State employees and PHARMA, not the  academics.  But the academics in all of these trials have been way too tied into industry across the  board. These studies have generated a lot of money for participating universities and centers &#8211; over $50 M from the NIMH alone. In Academia, there&#8217;s a <em>commerce<\/em> in published articles and <font color=\"#200020\">STAR*D <\/font>probably hit an all time high with well over 100 papers, each with way too many authors [see <a href=\"http:\/\/1boringoldman.com\/index.php\/2011\/04\/14\/infectious-numerology\/\" target=\"_blank\">infectious numerology&#8230;<\/a>]. Then in the <font color=\"#200020\">iSPOT<\/font> byline, we see some&nbsp; legendary psychiatrist entrepreneurs [Nemeroff, Schatzberg, Debattista]. Also, there&#8217;s Evian Gordon&#8217;s more up front private enterprises hoping to develop commercial tests to screen patients to pick an antidepressant in advance, as in this BrainNet&#8217;s pitch [see <a href=\"http:\/\/1boringoldman.com\/index.php\/2011\/04\/21\/personalized-medicine-beyond-the-blockbuster-era\/\" target=\"_blank\">personalized medicine: beyond blockbusters&hellip;<\/a>]:<\/div>\n<p align=\"center\" class=\"small\"><img decoding=\"async\" border=\"0\" width=\"450\" src=\"http:\/\/1boringoldman.com\/images\/pm-7.gif\" \/><\/p>\n<div align=\"justify\" class=\"small\"> Note: this document is now gone from the Internet [see it currently <a href=\"http:\/\/web.archive.org\/web\/20110216032212\/http:\/\/test.brainresource.com\/files\/Integrative%20Platform%20for%20New%20Drug%20Discovery.pdf\" target=\"_blank\">here<\/a> through the Wayback Machine].<\/div>\n<\/td>\n<\/tr>\n<tr>\n<td align=\"center\">\n<hr size=\"1\" \/><strong><font color=\"#200020\">DESIGN<\/font><\/strong>        <\/p>\n<hr size=\"1\" \/><\/td>\n<\/tr>\n<tr>\n<td>\n<div align=\"justify\" class=\"small\">These studies have not been designed like the usual RCTs. For example, <strong><font color=\"#660033\">none had a placebo group<\/font><\/strong>, so the response\/remission rates were uncorrected for the usual improvements seen in antidepressant trials from inert treatment [placebo]. As a result, the strength of drug effect [NNT, NNH, Odds Ratios, Effect Size] simply could not be calculated, was an unknown. None of them have followed the usual double-blinding, settling for partial schemes of one sort or another. They were described as &quot;naturalistic&quot; &#8211; meaning more like the treatment one might receive in a office situation than a strict controlled trial [and it showed]. They had high drop-out rates and there&#8217;s a lot of confusion about the various rating instruments used, particularly with <font color=\"#200020\">STAR*D<\/font> [see <a target=\"_blank\" href=\"http:\/\/1boringoldman.com\/index.php\/2011\/04\/06\/recalculating\/\">recalculating&hellip;<\/a>&nbsp; and <a target=\"_blank\" href=\"http:\/\/1boringoldman.com\/index.php\/2011\/04\/06\/still-recalculating\/\">still recalculating&hellip;<\/a>]. Thus far, the only completely reported study was<font color=\"#200020\"> CO-MED<\/font> [a negative trial]. In spite of a flood of offshoot papers, the final report for STAR*D never appeared, and the results that were reported begged <a target=\"_blank\" href=\"http:\/\/1boringoldman.com\/index.php\/2011\/04\/03\/a-thirty-five-million-dollar-misunderstanding\/\">credibility<\/a>. <\/div>\n<\/td>\n<\/tr>\n<\/table>\n<p align=\"justify\" class=\"small\">I started this post intending to comment on the preliminary <font color=\"#200020\">iSPOT<\/font> study reported above, but thought I ought to remind us about the history of these two studies [<font color=\"#200020\">iSPOT<\/font> and <font color=\"#200020\">EMBARC<\/font>] that are part of a quest to find biomarkers that will predict response to antidepressants. What I really wanted to do was describe the rationale for thinking that such biomarkers might exist, but looking back over the literature, I can&#8217;t find any rationale. Like the efforts of these investigators in earlier outings that looked at various algorithms and guidelines that explored sequencing, combining, or augmenting antidepressant regimens, scientific rationale is missing. Certainly those outings [<font color=\"#200020\">TMAP, STAR*D, IMPACTS, <\/font>and<font color=\"#200020\"> CO-MED<\/font>] have yielded nothing of note. And yet there are two major ongoing studies with authors familiar to all of us, all hotly pursuing this line of investigation. Perhaps, that&#8217;s the more interesting question than the actual studies themselves, <em>Why do they persist in going down this road?<\/em> <em>Why do they keep trying to find a way to make these drugs more effective than they are, with no scientific clues that it&#8217;s possible?<\/em> <em>Why are these efforts funded?<\/em><\/p>\n<div align=\"justify\" class=\"small\">Maybe I&#8217;ll take a shot at those questions, but first I&#8217;m going to stick to my guns and report on the<font color=\"#200020\"> iSPOT<\/font> study in the next post like I planned in this one [before I got wordy with my skepticism], because this report deserves some clarification of its own&#8230;<\/div>\n","protected":false},"excerpt":{"rendered":"<p>The International Study to Predict Optimized Treatment in Depression [iSPOT-D]: Outcomes from the acute phase of antidepressant treatment by Saveanu R, Etkin A, Duchemin AM, Goldstein-Piekarski A, Gyurak A, Debattista C, Schatzberg AF, Sood S, Day CV, Palmer DM, Rekshan WR, Gordon E, Rush AJ, Williams LM. Journal of Psychiatric Research. 2015 61:1-12. We aimed [&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_forum_subforum_count":0,"footnotes":""},"categories":[5],"tags":[],"class_list":["post-54185","post","type-post","status-publish","format-standard","hentry","category-opinion"],"_links":{"self":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/54185","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=54185"}],"version-history":[{"count":102,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/54185\/revisions"}],"predecessor-version":[{"id":54327,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/54185\/revisions\/54327"}],"wp:attachment":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/media?parent=54185"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/categories?post=54185"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/tags?post=54185"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}