{"id":17388,"date":"2011-12-19T21:42:18","date_gmt":"2011-12-20T02:42:18","guid":{"rendered":"http:\/\/1boringoldman.com\/?p=17388"},"modified":"2011-12-20T04:58:18","modified_gmt":"2011-12-20T09:58:18","slug":"what-was-that-all-about","status":"publish","type":"post","link":"https:\/\/1boringoldman.com\/index.php\/2011\/12\/19\/what-was-that-all-about\/","title":{"rendered":"what was that all about?<\/em>…"},"content":{"rendered":"
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Randomized, Placebo-Controlled Trials of Antidepressants for Acute Major Depression: Thirty-Year Meta-Analytic Review <\/font><\/strong>
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

This has been an odd era – one in which Clinical Drug Trials have reigned supreme. 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]. The 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\n\n
With apologies, I have altered this table from the study by adding the more familiar Brand Names on the right, removing the numeric values, and color-coding in the drug classes. They considered the Nardil and Anafranel values outliers [to be ignored]. The box size is proportional to the number of studies. The line is the 95% Confidence Interval.
<\/sup><\/td>\n<\/tr>\n<\/table>\n

Without considering other factors, the results are ironic – the first two drugs [introduced 50 years ago], Tofranil and Elavil, are the most efficacious:<\/p>\n

<\/p>\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

As you can see, in these Clinical Trials, there’s no change trend in the drug responders [Drug Responders (%)<\/strong><\/em>], but there’s a dramatic change trend in the placebo responders [Placebo Responders (%)<\/strong><\/em>]. There is an equally impressive increase in subjects and sites per study over the years [left-most graphs].<\/p>\n

The authors conclude "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" [see the graphs on the far right]. Surely that’s correct – particularly "better quality-control of diagnostic and clinical assessments." The escalating number of subjects and sites is, in part, an attempt to compensate for the epidemic of placebo responders. They also conclude that "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<\/font><\/strong>" which also seems intuitively true. <\/p>\n

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These thoughts below the line are mine, not from these authors<\/em>. People talk about the problem of the increasing placebo effect over the years as if it’s a great mystery. I don’t see it as any mystery at all. It parallels the rise of the Clinical Research Industry with Clinical Research Organizations and Clinical Research Centers scattered far and wide over the globe. These aren’t the clinically depressed patients that come to our offices. They’re another breed – a heterogeneous collage of people recruited from who-knows-where to be in a study. In spite of the fact that they seem to be trying to hide the source of patients, it doesn’t take long to recognize that these are hardly the DSM-IV MDD patients advertised – rather ad responders, students, pros, characterologic<\/em> patients, the curious, etc. While I’m sympathetic with the problem of finding subjects, the way it’s being done makes the studies suspect right out of the gate. That’s my view of the "placebo effect" changes. <\/p>\n

One thing this study leaves out is the other reason for so many sites. The Clinical Research Organizations advertise a rapid time-to-market<\/font><\/strong>. One way to do that is to call on multiple sites to come up with a few cases each. I haven’t seen any publications that study that part.  I tried to look at it myself. I don’t have access to enough data to do anything definitive. But I did look at the Seroquel trials on clinicaltrials.gov over the years. They shortened the study duration by ‘globalization’:<\/p>\n

<\/p>\n

My guess is that this trend would be reflected in other studies as well both by ‘globalization’ and increasing the number of sites [but it’s not for some blogger on a mountain in Georgia to prove]. My point is only that all of this weirdness in Clinical Trial data is hardly supernatural. It’s obviously because the Clinical Trials are being done in a weird way that’s focused specifically on getting statistical significance rapidly on the way to market rather that a heartfelt attempt at measuring efficacy, toxicity, and robustness.<\/p>\n

As a clinician, I spent much of the last 25 years actually thinking that the SSRIs were both more efficacious and less toxic than the TCAs that preceded them. I didn’t believe that because I was a biological psychiatrist caught up in the whirlwind of the psychopharmacological revolution. It was just part of the general lore of the specialty. Both of those things were, in fact, wrong. I steered clear of certain of the SSRI\/SNRI drugs because of withdrawal syndromes, but I didn’t learn about those things from the literature. I was made aware by seeing patients who’d had bad experiences. As a practicing psychiatrist, the things I’d relied on in the past to keep me up to speed on drugs, old and new, misinformed<\/font><\/strong> me. The intuition I had for what was science and what was advertisement no longer functioned as it had earlier in my career. In former days, I could count on Clinical Trials in peer-reviewed journals being performed on patients with the disorders listed in the article. I could no longer count on that being true. I could count on academic experts. Not any more. There was no solid ground. I would have been better off prescribing exactly as I had in 1977 when I finished my residency – TCA antidepressants, first generation antipsychotics, Lithium Carbonate, and Benzodiazepines [for anxiety that had to be treated].<\/font><\/strong> <\/p>\n

Marlon Brando once said that he didn’t want to be lying on his deathbed thinking, "What was that<\/u> all about?<\/font><\/em><\/strong>" Well that is<\/u> how I think about a lot of the psychiatry that preoccupied the post DSM-III [1980] world. "What was that<\/u> all about?<\/font><\/strong><\/em>"…<\/div>\n","protected":false},"excerpt":{"rendered":"

Randomized, Placebo-Controlled Trials of Antidepressants for Acute Major Depression: Thirty-Year Meta-Analytic Review by Juan Undurraga and Ross J Baldessarini Neuropsychopharmacology [advance online publication] 14 December 2011 Abstract: 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, […]<\/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-17388","post","type-post","status-publish","format-standard","hentry","category-politics"],"_links":{"self":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/17388","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=17388"}],"version-history":[{"count":54,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/17388\/revisions"}],"predecessor-version":[{"id":17441,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/17388\/revisions\/17441"}],"wp:attachment":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/media?parent=17388"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/categories?post=17388"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/tags?post=17388"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}