{"id":14314,"date":"2011-10-04T22:49:18","date_gmt":"2011-10-05T02:49:18","guid":{"rendered":"http:\/\/1boringoldman.com\/?p=14314"},"modified":"2011-10-04T22:49:18","modified_gmt":"2011-10-05T02:49:18","slug":"first-rate-madness","status":"publish","type":"post","link":"https:\/\/1boringoldman.com\/index.php\/2011\/10\/04\/first-rate-madness\/","title":{"rendered":"first rate madness…"},"content":{"rendered":"\n

Fall is just getting going here in the mountains. Some cool mornings, the dogwood leaves are turning a dark red. It’s too soon to know if this is going to be one of those breathtakingly beautiful seasons or if it’ll be a race to brown. I can’t ever predict, but I spout theories anyway, "been a rainy summer so…" etc. I’m teaching a course every weekend for the month and am a little preoccupied with that. Fall visitors come and go. Cooking pork for the Fall Social this Saturday. But I’m in a kind of waiting mode. Waiting for what? The TMAP Trial in November, for one thing. And I wonder what’s going to happen in Australia with all of that medicating ‘Ultra High Risk’ patients. But I think the big picture is that I’m wanting something to happen to start putting a closing parentheses on what I consider to be a dark time in the history of psychiatry. It’s not like some election is going to happen and we will have a new administration [though that would be nice]. I don’t even know what it might be that would mark such a change. But I’m waiting for it never-the-less.<\/font><\/em><\/p>\n

This post isn’t about that "it." This one is about something I saw on Med<\/font><\/em>Scape<\/font><\/strong> the other day, but it starts with this PLoS<\/font><\/strong> article from a couple of years ago:<\/div>\n
\n
Initial Severity and Antidepressant Benefits:<\/font><\/strong><\/u><\/a><\/div>\n
A Meta-Analysis of Data Submitted to the Food and Drug Administration<\/font><\/strong><\/u><\/a>
by Irving Kirsch, Brett J. Deacon, Tania B. Huedo-Medina, Alan Scoboria, Thomas J. Moore, Blair T. Johnson<\/sup>
PLoS Medicine<\/font><\/strong> 2008 5[2]:260-269.
[full text on-line]<\/font><\/strong><\/u><\/a><\/div>\n

<\/p>\n

Background<\/font><\/strong><\/u>: Meta-analyses of antidepressant medications have reported only modest benefits over placebo treatment, and when unpublished trial data are included, the benefit falls below accepted criteria for clinical significance. Yet, the efficacy of the antidepressants may also depend on the severity of initial depression scores. The purpose of this analysis is to establish the relation of baseline severity and antidepressant efficacy using a relevant dataset of published and unpublished clinical trials.
Methods and Findings<\/font><\/strong><\/u>: We obtained data on all clinical trials submitted to the US Food and Drug Administration [FDA] for the licensing of the four new-generation antidepressants for which full datasets were available. We then used meta-analytic techniques to assess linear and quadratic effects of initial severity on improvement scores for drug and placebo groups and on drug–placebo difference scores. Drug–placebo differences increased as a function of initial severity, rising from virtually no difference at moderate levels of initial depression to a relatively small difference for patients with very severe depression, reaching conventional criteria for clinical significance only for patients at the upper end of the very severely depressed category. Meta-regression analyses indicated that the relation of baseline severity and improvement was curvilinear in drug groups and showed a strong, negative linear component in placebo groups.
Conclusions<\/font><\/strong><\/u>: Drug–placebo differences in antidepressant efficacy increase as a function of baseline severity, but are relatively small even for severely depressed patients. The relationship between initial severity and antidepressant efficacy is attributable to decreased responsiveness to placebo among very severely depressed patients, rather than to increased responsiveness to medication.<\/font><\/strong><\/sup><\/div>\n<\/blockquote>\n
<\/div>\n
In their meta-analysis, they looked at all the studies turned in to the FDA for the major antidepressants, not just the published studies. And they defined criteria for clinical significance rather than statistical significance. A quick look at the graphs [HAM-D Improvement vs HAM-D Baseline] shows the green Clinical Significance boxes sparsely populated, and that the changes were from a drooping Placebo curve, not a rising Drug curve [whatever that might mean]. This study is what many critics are referring to when they say "antidepressants don’t work except in severe depression." One of this month’s Med<\/font><\/em>Scape<\/font><\/strong> pieces sets out to debunk the debunking [un-debunk the debunking?]: <\/div>\n
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The floor effect: Or why it’s hard to show anything works in mild depression<\/font><\/strong><\/u><\/a>
Med<\/font><\/em>Scape<\/font><\/strong>
by Nassir Ghaemi, MD
September 26, 2011<\/div>\n

The debates about antidepressant controversy have involved many issues.  One that has received little attention is the issue of a floor effect.  In the most popularized review<\/font><\/a><\/u><\/strong> of antidepressant randomized clinical trial [RCTs] in the FDA database, the conclusion was that antidepressants are ineffective except in the most extreme depressive episodes.  This was based on an analysis that for mild depression, antidepressants had almost the same effect as placebo. These comparisons are made using the Hamilton Depression Rating Scale [HDRS], a 17 item scale where 18 points is seen as the minimum score for a major depression, less than 24 is seen as mild depression, 24-28 is moderate, and above 28 is severe [with maximal score of 52]. In the above meta-analysis, the antidepressant group improved by 9.6 points from a baseline of 25.5.  The placebo group improved by 7.8 points.  The difference between the two groups of 1.8 points was seen as small, since the cut off for clinical significance was seen as 3 points. Hence the conclusion: antidepressants don’t work.  When assessed by severity of baseline depression, those with severe depression had a benefit with antidepressant over placebo above 3 points, but only if the baseline HDRS score was above 28.  Since most patients in most studies had lower scores, the authors concluded that antidepressants are not giving more benefit than nonspecific placebo effects in most patients.<\/sup><\/p>\n

The statistical floor effect is this:  If I start with a HDRS score of 50, and improve by 50% to a final score of 25, that is a 25 point improvement.  But if I start with a HDRS score of 20 and improve by 50% to a final score of 10, that is only a 10 point improvement.  The same relative effect of 50% improvement produces a smaller absolute effect when the depression scale starts at a lower number. There is a floor to how much benefit one can see in absolute depression scores. It may be, then, that the apparent lower benefit from mild depression has a similar explanation.  Recently, my colleague Paul Vohringer and I conducted an analysis of this question; we converted all the studies in the above meta-analysis to a percent improvement score on the HDRS, rather than absolute change in HDRS points.  In so doing, we also converted the 3 point difference – the standard of clinical significance – to a relative equivalent, which turned out to be about 12% difference between antidepressant and placebo.<\/sup><\/p>\n

In an analysis which is in press, we found the following:  the difference between antidepressant and placebo for mild depression [HDRS below 24] was only about 5%, which is far below the clinical significance threshold.  For severe depression [HDRS above 28] it was 16%, which is above that threshold.  So far, our results agree with the original meta-analysis.  But for moderate depression [HDRS between 24 and 28], the result was a 12% difference. Thus, when corrected for relative change, antidepressants have clinically significant benefits for moderate depression as well as severe depression, and this would include the majority of patients included in the FDA studies. The original meta-analysis concluded, with much ballyhoo in the mainstream media, that antidepressants are not effective in most patients, except in a minority with the most extreme depressions. That conclusion did not correct for the clear statistical fact that it is more difficult to show absolute differences with lower depression scores – a floor effect.  After correcting for that floor effect by looking at change in relative, not absolute terms, these results would indicate that antidepressants are effective in many patients – at least acutely – except in the mildest depressions.<\/font><\/strong><\/sup><\/div>\n<\/blockquote>\n
Dr. Ghaemi [Professor of Psychiatry and Pharmacology at Tufts Medical Center] is an interesting character – often on the perverse side of things. He’s got a recent book, A First-Rate Madness: Uncovering the Links between Leadership and Mental Illness<\/font><\/a><\/strong><\/u>, about political figures [dangerous shoals]. He endeared himself to me forever [selling seroquel VII: indication sprawl…<\/font><\/a><\/strong><\/u>] by responding to an AstraZeneca<\/font><\/strong> invitation to be a guest author by saying he’d do it if he got to actually see all the data and review all the analyses [what a concept!]. Needless to say, he was un-invited. His hypothesis in this presentation is simple, that we should use %-Improvement [relative change] instead of absolute change in the HAM-D scale to measure improvement. So now everything’s fine. Antidepressants work again. All’s right with the world. <\/div>\n

<\/p>\n

Has our literature over the decades since the introduction of the SSRIs been so corrupted that we don’t really even know if antidepressants are efficacious in depressed people? Do we have to do meta-analysis of meta-analyses to answer this most basic of questions? Does changing how we compute the HAM-D scores have anything to do with how patients have fared on these medications? Speaking of first-rate madness…<\/div>\n","protected":false},"excerpt":{"rendered":"

Fall is just getting going here in the mountains. Some cool mornings, the dogwood leaves are turning a dark red. It’s too soon to know if this is going to be one of those breathtakingly beautiful seasons or if it’ll be a race to brown. I can’t ever predict, but I spout theories anyway, "been […]<\/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-14314","post","type-post","status-publish","format-standard","hentry","category-politics"],"_links":{"self":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/14314","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=14314"}],"version-history":[{"count":42,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/14314\/revisions"}],"predecessor-version":[{"id":14356,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/14314\/revisions\/14356"}],"wp:attachment":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/media?parent=14314"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/categories?post=14314"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/tags?post=14314"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}