{"id":14609,"date":"2011-10-09T16:14:51","date_gmt":"2011-10-09T20:14:51","guid":{"rendered":"http:\/\/1boringoldman.com\/?p=14609"},"modified":"2011-10-09T21:23:21","modified_gmt":"2011-10-10T01:23:21","slug":"the-null-hypothesis","status":"publish","type":"post","link":"https:\/\/1boringoldman.com\/index.php\/2011\/10\/09\/the-null-hypothesis\/","title":{"rendered":"the null hypothesis&#8230;"},"content":{"rendered":"<ul>\n<div><em><font color=\"#999955\">How many roads must a man walk down &#8230;<br \/>        The answer my friend is blowing in the wind&#8230;<\/font><\/em><\/div>\n<\/ul>\n<div align=\"justify\">There is a persistent assumption that drug choice for the treatment of depression can be based on something other than adverse effects &#8211; that some people might preferentially respond to one or another drug or class of antidepressants. While there are allusions that this hypothesized differential response may have etiologic implications, often it is assumed with no reason being given. It is a persistent [and expensive] thought pursued for over a decade [without notable success]:<\/div>\n<div align=\"center\"><img loading=\"lazy\" decoding=\"async\" width=\"450\" vspace=\"7\" border=\"0\" height=\"263\" src=\"http:\/\/1boringoldman.com\/images\/prefer.gif\" \/><\/div>\n<div align=\"justify\">The first three versions were from algorithms that were based on the opinions of their designers as best I could tell when I reviewed them in the Spring [<strong><a target=\"_blank\" href=\"http:\/\/1boringoldman.com\/index.php\/2011\/05\/30\/algorithmic-psychiatry-the-algorithms\/\"><font color=\"#200020\">algorithmic psychiatry &ndash; the algorithms&hellip;<\/font><\/a><\/strong>]. Here they are from a distance to show their complexity. Click on the images to see the full-sized versions:<\/div>\n<div align=\"center\"><a href=\"http:\/\/archpsyc.ama-assn.org\/cgi\/reprint\/61\/7\/669.pdf#page=3\" target=\"_blank\"><img loading=\"lazy\" decoding=\"async\" width=\"175\" vspace=\"7\" border=\"0\" height=\"234\" src=\"http:\/\/1boringoldman.com\/images\/flow-tmap-2.gif\" \/><\/a><a href=\"http:\/\/ajp.psychiatryonline.org\/cgi\/content\/abstract\/163\/11\/1905\" target=\"_blank\"><img decoding=\"async\" vspace=\"7\" border=\"0\" hspace=\"17\" height=\"234\" src=\"http:\/\/1boringoldman.com\/images\/flow-star-d-2.gif\" \/><\/a><a href=\"http:\/\/www.biomedcentral.com\/content\/supplementary\/1472-6947-9-6-S1.pdf#page=3\" target=\"_blank\"><img decoding=\"async\" vspace=\"7\" border=\"0\" height=\"234\" src=\"http:\/\/1boringoldman.com\/images\/flow-impacts-2.gif\" \/><\/a><\/div>\n<div align=\"justify\"><strong><font color=\"#660033\">TMAP<\/font><\/strong> wasn&#8217;t a study [more like a scam]; <u><a target=\"_blank\" href=\"http:\/\/1boringoldman.com\/index.php\/2011\/04\/03\/a-thirty-five-million-dollar-misunderstanding\/\"><strong><font color=\"#660033\">STAR-D<\/font><\/strong><\/a><\/u> was unintelligible; and <u><a target=\"_blank\" href=\"http:\/\/1boringoldman.com\/index.php\/2011\/05\/28\/algorithmic-psychiatry-%E2%80%93-the-fall%E2%80%A6\/\"><strong><font color=\"#660033\">IMPACTS<\/font><\/strong><\/a><\/u> was never even completed. Having failed to get anywhere with arbitrary algorithms, they followed things up with <u><a href=\"http:\/\/1boringoldman.com\/index.php\/2011\/05\/03\/another-dud\/\" target=\"_blank\"><strong><font color=\"#660033\">CO-MED<\/font><\/strong><\/a><\/u> &#8211; an NIMH funded study using two antidepressant medications at the same time. It was a study&nbsp; where depressed subjects were tried  on monotherapy versus two-drugs therapy. There was no Placebo group.  The three groups in the study were:<\/div>\n<ul>\n<li>\n<div align=\"justify\">Escitalopram [<strong><font color=\"#200020\">Lexapro<\/font><\/strong>] Plus <strong><font color=\"#200020\">Placebo<\/font><\/strong> (N=224)<\/div>\n<\/li>\n<li>\n<div align=\"justify\">Sustained-Release Bupropion [<strong><font color=\"#200020\">Wellbutrin SR<\/font><\/strong>] Plus Escitalopram [<strong><font color=\"#200020\">Lexapro<\/font><\/strong>] (N=221)<\/div>\n<\/li>\n<li>\n<div align=\"justify\">Extended-Release Venlafaxine [<strong><font color=\"#200020\">Effexor XR<\/font><\/strong>] Plus Mirtazapine [<strong><font color=\"#200020\">Remeron<\/font><\/strong>] (N=220)<\/div>\n<\/li>\n<\/ul>\n<div align=\"justify\">Unlike the algorithm studies, <a href=\"http:\/\/1boringoldman.com\/index.php\/2011\/05\/03\/another-dud\" target=\"_blank\"><strong><font color=\"#660033\">CO-MED<\/font><\/strong><\/a> was definitive:<\/div>\n<div align=\"center\"><img loading=\"lazy\" decoding=\"async\" width=\"520\" vspace=\"7\" border=\"0\" height=\"196\" src=\"http:\/\/1boringoldman.com\/images\/co-med-3.gif\" \/><\/div>\n<div align=\"justify\">It was a an exuberant failure &#8211; no differences found. So having found nothing in their first decade of sequencing and commingling antidepressants in an attempt to increase their efficacy, one might think that they&#8217;d move on and come up with something else to think about. While there are a sea of authors&#8217; names on these studies, I&#8217;m speaking here of the principles <strong><font color=\"#200020\">Dr. A.J. Rush<\/font><\/strong> and <strong><font color=\"#200020\">Dr. M.H. Trivedi<\/font><\/strong> both at U.T. Southwestern at the time. But some ideas die slowly, it seems.<\/div>\n<p align=\"justify\">I know that I perseverate on these particular studies, but it seems to me that rather than apologize, I should be wondering instead why it isn&#8217;t an international pastime. These four outings have cost millions [or more]. The <strong><font color=\"#660033\">TMAP<\/font><\/strong> algorithms cost the State of Texas [and other States] an untold amount of money [hopefully revealed in the coming trial in the suit against <strong><font color=\"#990000\">J&amp;J<\/font><\/strong> in November]. <strong><font color=\"#660033\">STAR*D<\/font><\/strong> came in at $35 M and neither <strong><font color=\"#660033\">IMPACTS<\/font><\/strong> nor <strong><font color=\"#660033\">CO-MED<\/font><\/strong> came cheap [all three on the NIMH nickle]. For the last several weeks, I&#8217;ve been roaming around the next two offerings [<a target=\"_blank\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC3036635\/\"><strong><font color=\"#000099\">iSPOT<\/font><\/strong><\/a> and <a target=\"_blank\" href=\"http:\/\/projectreporter.nih.gov\/project_info_description.cfm?projectnumber=1U01MH092221-01\"><u><strong><font color=\"#2200aa\">Trivedi&#8217;s NIMH study<\/font><\/strong><\/u><\/a>] focusing on their hopes that some genetic bio-markers will be found that will direct treatment. But both studies have other aspects besides just sending samples to the genomics laboratories. Paradoxically, these are the studies that should have come <u>before<\/u> the ones already mentioned.<\/p>\n<ol>\n<div><strong><font color=\"#2200aa\"><u>Trivedi&#8217;s NIMH study<\/u> [EMBARC]:<\/font><\/strong><\/div>\n<ul>\n<div align=\"justify\">This study began as a comparison among <strong><font color=\"#200020\">Citalopram<\/font><\/strong>, <strong><font color=\"#200020\">Bupropion<\/font><\/strong>, and <strong><font color=\"#200020\">Cognitive Behavior Therapy<\/font><\/strong> [<a href=\"http:\/\/projectreporter.nih.gov\/project_info_description.cfm?aid=8014460&#038;icde=10031915\" target=\"_blank\"><u><strong><font color=\"#000099\">RePORTER<\/font><\/strong><\/u><\/a>], but by the time it was registered as a Clinical Trial [July 25, 2011], it had become a comparison among <strong><font color=\"#200020\">Citalopram<\/font><\/strong>, <strong><font color=\"#200020\">Bupropion<\/font><\/strong>, and <strong><font color=\"#200020\">Placebo<\/font><\/strong>. [<u><a href=\"http:\/\/clinicaltrials.gov\/ct2\/show\/NCT01407094\" target=\"_blank\"><strong><font color=\"#000099\">clinicaltrials.gov<\/font><\/strong><\/a><\/u>]. It has the <a href=\"http:\/\/www.stat.lsa.umich.edu\/%7Esamurphy\/nida\/CPDDAlmirall2011.pdf\" target=\"_blank\"><u><strong><font color=\"#200020\">SMART<\/font><\/strong><\/u><\/a> design motif [<strong><font color=\"#200020\">sequential multiple-assignment randomized trial<\/font><\/strong>], meaning that non-responders are then switched to the <em>other<\/em> treatment. So it&#8217;s another drug sequencing scheme. It now has a name and a <a href=\"http:\/\/embarc.utsouthwestern.edu\/\" target=\"_blank\"><u><strong><font color=\"#200020\">website<\/font><\/strong><\/u><\/a> [<strong><font color=\"#2200aa\">EMBARC<\/font><\/strong> &#8211; Establishing Moderators\/Mediators for a Biosignature of Antidepressant                                          Response in Clinical Care]. They plan to &quot;<em>&#8230;<\/em><em>assess a comprehensive array of carefully selected  clinical (i.e. anxious depression, early life trauma, &amp; gender) and  biological (i.e. genetic, neuroimaging, serum, epigenetic &amp; qEEG)  moderators and mediators of outcome. Using innovative statistical  approaches the identified moderators and mediators will then be used to  develop a differential depression treatment response index (DTRI)<\/em>&#8230; <em>The DTRI will help clinicians match treatments to patients with  MDD, resulting in timely selection of treatments best suited for  individual patients.<\/em>&quot;<\/div>\n<\/ul>\n<div><strong><font><strong><font color=\"#000099\"><u>International Study to Predict Optimized Treatment for Depression<\/u> [iSPOT]:<\/font><\/strong><\/font><\/strong><\/div>\n<ul>\n<div align=\"justify\">The <a target=\"_blank\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC3036635\/\"><strong><font color=\"#000099\">iSPOT<\/font><\/strong><\/a> design is different. They are comparing <strong><font color=\"#200020\">Escitalopram<\/font><\/strong>, <strong><font color=\"#200020\">Sertraline<\/font><\/strong>, and <strong><font color=\"#200020\">Venlafaxine-XR<\/font><\/strong> [without a <strong><font color=\"#200020\">Placebo<\/font><\/strong> group]. After phase I, they plan to analyze the many parameters they are measuring and develop biomarker driven algorithms to use in a repeat phase II study. Their Clinical Trial is underway [<u><a href=\"http:\/\/clinicaltrials.gov\/ct2\/show\/NCT00693849?term=ispot&#038;rank=2\" target=\"_blank\"><strong><font color=\"#000099\">clinicaltrials.gov<\/font><\/strong><\/a><\/u>], registered on June 6, 2008.       <\/div>\n<\/ul>\n<\/ol>\n<div align=\"justify\">So this time around, they&#8217;re measuring any and everything possible to try to find an algorithm that might work [at least the algorithms might be coming from data instead of just their opinions]. The <strong><font><strong><font color=\"#000099\">iSPOT<\/font><\/strong><\/font><\/strong> study is even brave enough to try out whatever they come up with. Trivedi is still in the driver&#8217;s seat of <strong><font color=\"#2200aa\">EMBARC<\/font><\/strong>. This time, Rush is on the sidelines [in <strong><font><strong><font color=\"#000099\">iSPOT<\/font><\/strong><\/font><\/strong>] with this assignment &#8211; &quot;<em>AJR is Chair of the iSPOT-D Publication Committee<\/em>&quot; [a fitting assignment since he got 100+ publications out of STAR*D] teamed with his STAR*D sidekick, &quot;<em>We gratefully acknowledge the editorial support of <a href=\"http:\/\/kilnerwriter.net\/published.htm\" target=\"_self\"><u><strong><font color=\"#200020\">Jon Kilner<\/font><\/strong><\/u><\/a>, MS, MA (Pittsburgh, PA, USA)<\/em>.&quot;<\/div>\n<p> <\/p>\n<div align=\"justify\">Will these two studies find something of enduring value? I really doubt it [with the genetics part, I <em>double-dog-doubt<\/em>  it for reasons I&#8217;ve run into the ground previously]. Will they finally  lead us to accept the null hypothesis that there&#8217;s no extra mileage to  be gotten out of the antidepressants than we already know? I certainly  hope so. The net amount of treasure spent testing them in trials,  against each other, in tandem, in combination, with augmentation, etc.  would run a small country&#8230;<\/div>\n","protected":false},"excerpt":{"rendered":"<p>How many roads must a man walk down &#8230; The answer my friend is blowing in the wind&#8230; There is a persistent assumption that drug choice for the treatment of depression can be based on something other than adverse effects &#8211; that some people might preferentially respond to one or another drug or class of [&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":[2],"tags":[],"class_list":["post-14609","post","type-post","status-publish","format-standard","hentry","category-politics"],"_links":{"self":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/14609","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=14609"}],"version-history":[{"count":11,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/14609\/revisions"}],"predecessor-version":[{"id":14621,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/14609\/revisions\/14621"}],"wp:attachment":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/media?parent=14609"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/categories?post=14609"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/tags?post=14609"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}