{"id":29279,"date":"2012-10-22T14:11:20","date_gmt":"2012-10-22T18:11:20","guid":{"rendered":"http:\/\/1boringoldman.com\/?p=29279"},"modified":"2012-10-22T14:55:35","modified_gmt":"2012-10-22T18:55:35","slug":"suggests-that-such-variants-do-not-exist","status":"publish","type":"post","link":"https:\/\/1boringoldman.com\/index.php\/2012\/10\/22\/suggests-that-such-variants-do-not-exist\/","title":{"rendered":"suggests that such variants do not exist&#8230;"},"content":{"rendered":"<div align=\"justify\">In a seemingly endless string of attempts to make the modern antidepressants more potent than they are, we went through <em>algorithm&middot;izing<\/em>, sequencing, combining, and augmenting with little to no improvement in efficacy. That was followed by personalized medicine [<a target=\"_blank\" href=\"http:\/\/1boringoldman.com\/index.php\/2011\/10\/05\/fool-me-twice-2\/\"><u><strong><font color=\"#200020\">fool me twice&hellip;<\/font><\/strong><\/u><\/a> etc], the notion that the response to antidepressants is genetically linked\/determined. While I can&#8217;t figure out why that would be true, given that combining antidepressants doesn&#8217;t add anything, it is none-the-less written about and studied all over the place [<a target=\"_blank\" href=\"http:\/\/www.brainresource.com\/research\/ispot\"><u><strong><font color=\"#200020\">iSPOT<\/font><\/strong><\/u><\/a>, <a target=\"_blank\" href=\"http:\/\/embarc.utsouthwestern.edu\/\"><u><strong><font color=\"#200020\">EMBARC<\/font><\/strong><\/u><\/a>] and already becoming commercially available [<strong><a target=\"_blank\" href=\"http:\/\/1boringoldman.com\/index.php\/2012\/10\/12\/take-a-look\/\"><u><font color=\"#200020\">take a look&hellip;<\/font><\/u><\/a><\/strong>]. My personal skepticism is a matter of public record. Comes now this report:    <\/div>\n<blockquote>\n<div align=\"center\"><a href=\"http:\/\/www.plosmedicine.org\/article\/info%3Adoi%2F10.1371%2Fjournal.pmed.1001326\" target=\"_blank\"><u><strong><font color=\"#200020\">Genetic Predictors of Response to Serotonergic and Noradrenergic Antidepressants in Major Depressive Disorder: A Genome-Wide Analysis of Individual-Level Data and a Meta-Analysis<\/font><\/strong><\/u><\/a><br \/>       <sup>by Katherine E. Tansey, Michel Guipponi, Nader Perroud, Guido Bondolfi, Enrico Domenici, David Evans, Stephanie K. Hall, Joanna Hauser, Neven Henigsberg, Xiaolan Hu, Borut Jerman, Wolfgang Maier, Ole Mors, Michael O&#8217;Donovan, Tim J. Peters, Anna Placentino, Marcella Rietschel, Daniel Souery, Katherine J. Aitchison, Ian Craig, Anne Farmer, Jens R. Wendland, Alain Malafosse, Peter Holmans, Glyn Lewis, Cathryn M. Lewis, Tine Bryan Stensb&oslash;l, Shitij Kapur, Peter McGuffin, and Rudolf Uher<\/sup><br \/>       <strong><font color=\"#200020\">PLoS Med<\/font><\/strong> 9[10]:e1001326. doi:10.1371\/journal.pmed.1001326.<br \/>   <sup>[<a target=\"_blank\" href=\"http:\/\/www.plosmedicine.org\/article\/info%3Adoi%2F10.1371%2Fjournal.pmed.1001326\"><u><strong><font color=\"#200020\">full text on-line<\/font><\/strong><\/u><\/a>]<\/sup><\/div>\n<p>     <\/p>\n<div align=\"justify\"><sup><strong><u><font color=\"#200020\">Background<\/font><\/u>: It has been suggested that outcomes of antidepressant treatment for major depressive disorder could be significantly improved if treatment choice is informed by genetic data. This study aims to test the hypothesis that common genetic variants can predict response to antidepressants in a clinically meaningful way.<br \/>        <u><font color=\"#200020\">Methods and Findings<\/font><\/u>: The NEWMEDS consortium, an academia&ndash;industry partnership, assembled a database of over 2,000 European-ancestry individuals with major depressive disorder, prospectively measured treatment outcomes with serotonin reuptake inhibiting or noradrenaline reuptake inhibiting antidepressants and available genetic samples from five studies [three randomized controlled trials, one part-randomized controlled trial, and one treatment cohort study]. After quality control, a dataset of 1,790 individuals with high-quality genome-wide genotyping provided adequate power to test the hypotheses that antidepressant response or a clinically significant differential response to the two classes of antidepressants could be predicted from a single common genetic polymorphism. None of the more than half million genetic markers significantly predicted response to antidepressants overall, serotonin reuptake inhibitors, or noradrenaline reuptake inhibitors, or differential response to the two types of antidepressants [genome-wide significance p&lt;5&times;10&minus;8]. No biological pathways were significantly overrepresented in the results. No significant associations [genome-wide significance p&lt;5&times;10&minus;8] were detected in a meta-analysis of NEWMEDS and another large sample [STAR*D], with 2,897 individuals in total. Polygenic scoring found no convergence among multiple associations in NEWMEDS and STAR*D.<br \/>       <u><font color=\"#200020\">Conclusions<\/font><\/u>: No single common genetic variant was associated with antidepressant response at a clinically relevant level in a European-ancestry cohort. Effects specific to particular antidepressant drugs could not be investigated in the current study.<\/strong><\/sup><\/div>\n<ul>\n<div align=\"justify\"><sup><strong><u><font color=\"#200020\">Editor&#8217;s Note<\/font><\/u>: The researchers selected 1,790 patients with severe depression who had participated in one of several research studies; 1,222 of the patients had been treated with an SRI, the remaining 568 with an NRI, and it was recorded how well the drugs worked for each patient. The researchers also had a detailed picture of the genetic make-up of each patient, with information for over half a million genetic variants. They then looked for an association between genetic variants and responses to drugs. They found not a single genetic variant that could predict clearly whether a person would respond to antidepressants in general, to one of the two main groups [SRIs and NRIs], or much better to one than the other. They also didn&#8217;t find any combination of variants in groups of genes that work together that could predict responses. Combining their data with those from another large study did not yield any robust predictors either. This study was large enough that it should have been possible to find common genetic variants that by themselves could predict a clinically meaningful response to SRIs and\/or NRIs, had such variants existed. The fact that the study failed to find such variants suggests that such variants do not exist. It is still possible, however, that variants that are less common could predict response, or that combinations of variants could. To find those, if they do exist, even larger studies will need to be done.<\/strong><\/sup><\/div>\n<\/ul>\n<\/blockquote>\n<div align=\"justify\">I fully admit that my skepticism was not just scientific, but based on the track record of the researchers who jumped at the concept &#8211; Nemeroff, Schatzberg, Rush, Trivedi, etc, people who have been too involved with pharmaceutical companies, too speculative in their biologizing, and published too many articles along the way. People involved with the$e enterpri$e$:<\/div>\n<div align=\"center\"><img loading=\"lazy\" decoding=\"async\" width=\"450\" height=\"263\" border=\"0\" src=\"http:\/\/1boringoldman.com\/images\/prefer.gif\" \/><\/div>\n<div align=\"justify\">My scientific skepticism starts with the fact that there&#8217;s no real evidence that sequencing, combining, or augmenting in garden variety MDD adds any efficacy. I can&#8217;t divine any reason that natural selection would create such a genetic system. And finally, I know of no evidence that suggests genetic control except for the variable response of depressed people to these drugs &#8211; and there are a gajillion other more likely reasons for that [variable conditions lumped as MDD, lousy drugs, personality disorders, life histories, etc]. But that aside, this article appears to me to be a state-of-the-art-slam-dunk refutation of the hypothesis. They had a huge subject cohort, well documented outcomes, and tested the genome every way but sideways. I doubt that there&#8217;s ever been a drug class in history that people have tried so hard or spent so much trying to turn up the efficacy. In the end, the SSRIs and SRNIs are WYSIWYG [what you see is what you get].<\/div>\n<div align=\"justify\">&nbsp;<\/div>\n<div align=\"justify\">While it should dampen the enthusiasm of those involved in the other ongoing studies, I doubt that it will. Both <a target=\"_blank\" href=\"http:\/\/www.brainresource.com\/research\/ispot\"><u><strong><font color=\"#200020\">iSPOT<\/font><\/strong><\/u><\/a> and <a target=\"_blank\" href=\"http:\/\/embarc.utsouthwestern.edu\/\"><u><strong><font color=\"#200020\">EMBARC<\/font><\/strong><\/u><\/a> seem to be aiming to add other parameters into the mix with the genetic studies in hopes of finding some kind of combo biosignatures to direct drug choice.&nbsp; But my skepticism remains very high. And we have much more important matters to think about in psychiatry and in patient care than further wild goo$e cha$e$&#8230;<\/div>\n<div align=\"justify\">\n<div align=\"right\"><sup><strong>hat tip to Rob Purssey <\/strong><img decoding=\"async\" height=\"30\" border=\"0\" align=\"middle\" src=\"http:\/\/1boringoldman.com\/images\/hat-tip.gif\" \/><\/sup><\/div>\n<\/div>\n","protected":false},"excerpt":{"rendered":"<p>In a seemingly endless string of attempts to make the modern antidepressants more potent than they are, we went through algorithm&middot;izing, sequencing, combining, and augmenting with little to no improvement in efficacy. That was followed by personalized medicine [fool me twice&hellip; etc], the notion that the response to antidepressants is genetically linked\/determined. While I can&#8217;t [&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-29279","post","type-post","status-publish","format-standard","hentry","category-politics"],"_links":{"self":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/29279","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=29279"}],"version-history":[{"count":28,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/29279\/revisions"}],"predecessor-version":[{"id":29308,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/29279\/revisions\/29308"}],"wp:attachment":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/media?parent=29279"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/categories?post=29279"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/tags?post=29279"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}