{"id":22060,"date":"2012-04-12T21:59:17","date_gmt":"2012-04-13T01:59:17","guid":{"rendered":"http:\/\/1boringoldman.com\/?p=22060"},"modified":"2012-04-12T22:02:07","modified_gmt":"2012-04-13T02:02:07","slug":"end-of-something","status":"publish","type":"post","link":"https:\/\/1boringoldman.com\/index.php\/2012\/04\/12\/end-of-something\/","title":{"rendered":"end of something…"},"content":{"rendered":"\n
Back around Christmas, I had looked at a meta-analysis of antidepressant drugs published in Neuropsychopharmacology [what was that all about?<\/em>…<\/font><\/a><\/strong><\/u>, <\/font>meta<\/font> meta meta<\/font> meta<\/font> meta<\/font> meta<\/font> meta…<\/font><\/a><\/u><\/strong>] that seemed pretty well done to me. I’ve reproduced the essential findings below. What reminded me of it was a comment in that peculiar American Psychiatric Foundation Summit I was reporting on yesterday [APF Convenes Unique Pipeline Summit<\/font><\/strong><\/u><\/a>]. In that article, Madhukar Trivedi was quoted as saying:<\/div>\n
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Mudhukar Trivedi, M.D., director of the mood disorders research program at the University of Texas Southwestern, observed that “we are creating a virtual world in which [psychiatric] trials are conducted in the [least-severely ill] patients by the least-qualified people, and then [we] are surprised by the placebo effect.” Consequently, the general public and part of the medical community believe that antidepressants are no better than placebo.<\/sup><\/div>\n<\/blockquote>\n
I will admit up front that I am no fan of Dr. Trivedi, and in this case found his comment especially odd because he’s famous for doing studies with no placebo group [STAR*D, CO-MED], so the placebo effect is always working in his favor. But I didn’t really understand what he meant by "a virtual world in which [psychiatric] trials are conducted in the [least-severely ill] patients by the least-qualified people, and then [we] are surprised by the placebo effect<\/em>" other than it was as usual for him – a piece of haughty sarcasm. But his quip reminded me of this meta-analysis so I went back and took a look: <\/div>\n
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Randomized, Placebo-Controlled Trials of Antidepressants for Acute Major Depression: Thirty-Year Meta-Analytic Review <\/font><\/strong><\/a><\/u>
by Juan Undurraga and Ross J Baldessarini<\/sup>
Neuropsychopharmacology<\/font><\/strong> [advance online publication]
14 December 2011<\/div>\n

<\/p>\n

Abstract<\/font><\/strong><\/u>: Antidepressant–placebo response-differences [RDs] in controlled trials have been declining, potentially confounding comparisons among older and newer drugs. For clinically employed antidepressants, we carried out a meta-analytic review of placebo-controlled trials in acute, unipolar, major depressive episodes reported over the past three decades to compare efficacy [drug–placebo RDs] of individual antidepressants and classes, and to consider factors associated with year-of-reporting by bivariate and multivariate regression modeling. Observed drug–placebo differences were moderate and generally similar among specific drugs, but larger among older antidepressants, notably tricyclics, than most newer agents. This outcome parallels selective increases in placebo-associated responses as trial-size has increased in recent years. Study findings generally support moderate efficacy of clinically employed antidepressants for acute major depression, but underscore limitations of meta-analyses of controlled trials for ranking drugs by efficacy. We suggest that efficiency and drug–placebo differences may be improved with fewer sites and subjects, and better quality-control of diagnostic and clinical assessments.<\/sup><\/div>\n<\/blockquote>\n

Undurraga and Baldessarini did a meta-analysis of the antidepressant drug trials for the last thirty years, ending up with only 116 candidates from over 2000 studies that met their criteria [placebo controlled, randomized, double blind trials]. They used the study RR<\/font><\/strong> [Response Rate] for comparison [if X<\/font><\/strong> = mean % fall in rating scale then Xdrug<\/sub> ÷ Xplacebo<\/sub> = RR<\/font><\/strong>]. <\/p>\n

<\/div>\n

But this paper went further [to the authors’ credit]. They looked at the year the study was done, and the values of  Xdrug<\/sub><\/font><\/strong> and Xplacebo <\/sub><\/font><\/strong>over the years [center two graphs]: <\/p>\n

<\/p>\n

I had further separated the Response Rates out by drug class by year: <\/p>\n

 <\/p>\n

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I like this study even more than the first time through. It was straight up with all their numbers in a table for anyone to see. Personally, it spanned my whole career. Specialty-wise, it spanned the post·DSM-III era. It was a big picture meta-analysis to be proud of. I had sort of dropped it in December because we hit the road for some holiday travels and in early January, we were off again to Texas for the JNJ Trial so I just forgot about it. Today, I had some other projects going and so those graphs sat on my second screen for numerous glances while I did some busy work in the center ring.<\/div>\n

There are several stories there. One is about the deterioration of the quality of clinical trials as they’ve been increasingly privatized<\/em> and farmed out<\/em> to the CROs using multiple sites and, I suspect, fewer and fewer patients<\/em> and more and more recruits.<\/em> So as much as I hate to admit it, now that I think about it, Trivedi is probably right, it is a ‘virtual world’ [I hasten to add that his studies – TMAP, IMPACT, STAR*D, CO-MED haven’t added much to the knowledge-base about the ‘real world’ either]. But another story is that things have certainly not improved with time, and all the creative novel<\/em> stuff hasn’t added much either – sequencing, doubling up, augmenting, etc. And I’m betting against genomic directed personalized drug picking too [iSPOT, EMBARC]. Antidepressant medications seem to have a roughly fixed efficacy. No great shakes, but not nothing. If they’d reserve them for Melancholics instead of the virtual disease MDD<\/em>, I expect they would look a whole lot better.<\/p>\n

I doubt that yelling at the pipeline is going to make any difference, like they could make it spit out some wished for miracle drug. Matter of fact, I’m not sure this particular group really wants a miracle drug, because then they’d be obsolete. With an empty pipeline they have nothing to talk about. With a miracle drug, they have nothing to talk about. The only way they have something is to have a stream of middling drugs like the ones we’ve had for the last thirty plus years. That’s also true for the CRO Industry – no trials = no industry. The Pharmaceutical companies seem to know that there’s nothing much for them in that kind of situation and are unlikely to stay in the game now that the gold rush<\/em> is over just to support lonely KOLs and CROs. This meta-analysis says to me that we are at the end of something – an era of sorts. I’m not sure the people at that APF Summit quite know that yet. There’s an inertia of motion that takes a while to slow down…<\/div>\n","protected":false},"excerpt":{"rendered":"

Back around Christmas, I had looked at a meta-analysis of antidepressant drugs published in Neuropsychopharmacology [what was that all about?…, meta meta meta meta meta meta meta…] that seemed pretty well done to me. I’ve reproduced the essential findings below. What reminded me of it was a comment in that peculiar American Psychiatric Foundation Summit […]<\/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-22060","post","type-post","status-publish","format-standard","hentry","category-politics"],"_links":{"self":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/22060","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=22060"}],"version-history":[{"count":18,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/22060\/revisions"}],"predecessor-version":[{"id":22080,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/22060\/revisions\/22080"}],"wp:attachment":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/media?parent=22060"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/categories?post=22060"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/tags?post=22060"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}