{"id":19710,"date":"2012-02-16T20:54:26","date_gmt":"2012-02-17T01:54:26","guid":{"rendered":"http:\/\/1boringoldman.com\/?p=19710"},"modified":"2012-02-16T20:56:58","modified_gmt":"2012-02-17T01:56:58","slug":"back-to-the-future-2","status":"publish","type":"post","link":"https:\/\/1boringoldman.com\/index.php\/2012\/02\/16\/back-to-the-future-2\/","title":{"rendered":"back to the future&#8230;"},"content":{"rendered":"\n<p align=\"justify\"><em>It hasn&#8217;t been <\/em><em><strong><font color=\"#200020\">the best of times<\/font><\/strong>, and we&#8217;re not far enough beyond to yet know if it has been <\/em><em><strong><font color=\"#200020\">the worst of times<\/font><\/strong>. All we really know is that it has been <\/em><em><strong><font color=\"#200020\">our times<\/font><\/strong>. I suppose that it&#8217;s always that way &#8211; one&#8217;s personal slice of history hasn&#8217;t really yet become history proper, it&#8217;s still officially the present. So editorial perspective remains heavily colored by the personal experience of the people who have lived it.<\/em> <\/p>\n<p align=\"justify\">As a physician psychiatrist, I&#8217;ve seen a lot of depressed people over the years, and the recommendations about how to help them have been a potpourri, at the least. Like most of us, a lot of what I&#8217;ve done has increasingly relied on the intuition of experience &#8211; successes, failures, mistakes &#8211; <em><strong><font color=\"#200020\">anecdotes<\/font><\/strong><\/em> they&#8217;re called [sometimes warmly and sometimes as an invective].<\/p>\n<div align=\"justify\">In a recent post, I was referring to Dr. Carrol&#8217;s editorial [<strong><a href=\"http:\/\/1boringoldman.com\/index.php\/2012\/02\/15\/an-ode-to-melancholia\/\" target=\"_blank\"><font color=\"#200020\">an ode to melancholia&hellip;<\/font><\/a><\/strong>]. One reason melancholia&#8217;s absence from the DSM-III, DSM-IV, and now DSM-5 is so a bad idea is that it is a place in psychiatry where we know how to help with some accuracy. In his words:<\/div>\n<ul><sup><\/p>\n<div align=\"justify\">At the same time, it must be said that the most widely used contemporary antidepressant drugs are of dubious value in treating melancholia, and the evidence base for their use in bipolar melancholia is even less secure. The selective serotonin reuptake inhibitor class of antidepressant drugs replaced earlier antidepressant drug classes in broad clinical practice for reasons of safety and tolerability, not for improved efficacy. Indeed, for treating moderate-to-severe depression, the tricyclic antidepressant drugs have an excellently low Number Needed to Treat for response of about three, compared with about nine or higher for selective serotonin reuptake inhibitors. The current focus on so-called treatment-resistant depression and on augmentation strategies may reflect chiefly the fact that patients with melancholia have failed to respond to a class of antidepressant drug that possesses suboptimal efficacy&#8230;<\/p>\n<p>          So, what is a clinician to do? If we pay attention to the epidemiologic data, melancholia in its unipolar and bipolar forms affects maybe 3&ndash;4% of the population at most, whereas estimates of MDD prevalence range up to 25% or higher. The default position has to be, do not miss cases of melancholia; learn how to recognize them sooner rather than later in their course; do not fail to treat them with a genuinely effective agent; and think hard before casually prescribing antidepressant drugs to nonmelancholic patients with MDD because that may be a formula for wasted resources, unnecessary side effects, and unproductive clinical management.<\/p><\/div>\n<p><\/sup><\/ul>\n<div align=\"justify\">It is in this area of the psychopharmacologic treatment of non-melancholic depression where most of the confusion lies &#8211; made infinitely more complicated by the&nbsp; pharmaceutical companies hawking their wares to psychiatrists, primary care physicians, and patients &#8211; particularly when the marketing is disguised as something else [<em>science<\/em>]. But we&#8217;re  finally coming to something like the end of an era. The patents are running out on the main wave of <em>the formerly new<\/em> antidepressants, so maybe we can begin to sort out their actual place in the medical pharmacopeia:<\/div>\n<div align=\"center\"><img decoding=\"async\" vspace=\"5\" border=\"0\" src=\"http:\/\/1boringoldman.com\/images\/bttf-2.gif\" \/><\/div>\n<div align=\"justify\">They&#8217;re not benign drugs, so their fate isn&#8217;t going to be to become OTC [over the counter] drugs. There&#8217;s the akathisia, suicidality piece up front and the back end withdrawal syndromes among many other things. They&#8217;re not like the antihistamines and H2 blockers that role right from designer status onto the ready-to-wear shelves. The question isn&#8217;t really <em>when <u>should<\/u> they be used<\/em>, at least not in my way of thinking. It&#8217;s more, <em>when does it actually help to use them?<\/em> The answer is somewhere between <em><strong><font color=\"#200020\">never<\/font><\/strong><\/em> and <em><strong><font color=\"#200020\">all the time<\/font><\/strong><\/em> &#8211; which is a pretty broad range. There have been a few studies along the way that actually address that question without necessarily starting with foregone conclusions:<\/div>\n<blockquote>\n<div align=\"center\"><a target=\"_blank\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/11799341\"><u><strong><font color=\"#200020\">Severity of depression and response to antidepressants and placebo: an analysis of the Food and Drug Administration database<\/font><\/strong><\/u><\/a>.<br \/>    <sup>by Khan A, Leventhal RM, Khan SR, and Brown WA.<\/sup><br \/>    <strong><font color=\"#200020\">Journal of Clinical Psychopharmacology<\/font><\/strong> 2002 22[1]:40-5.<\/div>\n<p>    <\/p>\n<div align=\"justify\"><sup>Some  studies suggest that more severely ill patients with depression respond  well to antidepressants and poorly to placebo, whereas those who are  mildly ill respond equally well to antidepressants and placebo. This  notion has implications for the design of clinical trials. To further  assess and substantiate these putative predictors of antidepressant and  placebo response, we assessed the Food and Drug Administration database  of 45 phase II and III antidepressant clinical trials. The frequency of  statistically significant differences between antidepressants and  placebo was higher in the trials that included patients with more severe  depression. In the antidepressant-treated groups, the magnitude of  symptom reduction was significantly related to mean initial Hamilton  Rating Scale for Depression [HAM-D] score; the higher the mean initial  HAM-D score, the larger the change. With placebo treatment, however, the  higher the mean initial HAM-D score, the smaller the change. Early  discontinuation was more frequent among patients whose mean initial  HAM-D scores were higher. These data may help inform the design of  future antidepressant clinical trials.<\/sup><\/div>\n<\/blockquote>\n<div align=\"center\"><img loading=\"lazy\" decoding=\"async\" width=\"500\" vspace=\"5\" height=\"194\" border=\"0\" src=\"http:\/\/1boringoldman.com\/images\/bttf-3.gif\" \/><\/div>\n<div align=\"justify\">In this reassessment of the FDA&#8217;s clinical trials of the new antidepressants, Khan et al concluded:<\/div>\n<blockquote>\n<div align=\"justify\"><sup>Our results suggest that the severity of depressive symptoms, as measured by mean initial HAM-D score, influences the outcome of randomized, double blind, placebo-controlled antidepressant clinical trials. Antidepressants&rsquo; effects seem more robust and placebos&rsquo; less so among patients with more severe depression.<\/sup><\/div>\n<\/blockquote>\n<div align=\"justify\">Then there was a more recent study using a similar research strategy by Kirsch et al:  <\/div>\n<blockquote>\n<div align=\"center\"><a target=\"_blank\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC2253608\/?tool=pubmed\"><u><strong><font color=\"#200020\">Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data           Submitted to the Food and Drug Administration<\/font><\/strong><\/u><\/a><br \/>                                 <sup>by Irving Kirsch, Brett J. Deacon, Tania B. Huedo-Medina, Alan Scoboria, Thomas J. Moore, and Blair T. Johnson<\/sup><br \/>           <strong><font color=\"#0033ff\">PLoS Medicine<\/font><\/strong>. 2008 5[2]: e45.<br \/>     [<a href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC2253608\/?tool=pubmed\" target=\"_blank\"><u><strong><font color=\"#200020\">full text on-line<\/font><\/strong><\/u><\/a>]<\/div>\n<p>         <\/p>\n<div align=\"justify\"><sup><u><strong><font color=\"#200020\">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.   <br \/>           <strong><u><font color=\"#200020\">Methods and Findings<\/font><\/u><\/strong>: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&ndash;placebo difference   scores. Drug&ndash;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.<br \/>          <u><strong><font color=\"#200020\">Conclusions<\/font><\/strong><\/u>:  Drug&ndash;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.<\/sup><\/div>\n<\/blockquote>\n<div align=\"justify\">\n<div align=\"center\"><img decoding=\"async\" border=\"0\" src=\"http:\/\/1boringoldman.com\/images\/bttf-1.gif\" \/><\/div>\n<\/div>\n<div align=\"justify\"><em>I&#8217;ve shown only one of three graphs that ought to be looked at if you really want to <\/em><em><u>study the study<\/u> to see if you agree with their conclusions.<\/em> What they did was gather all the clinical trials, published <strong><font color=\"#200020\">and unpublished<\/font><\/strong>, done on the main antidepressants by querying the FDA where all trials <em>have to be<\/em> reported. So that graph is the mean HAM-D improvement against the initial HAM-D Score [the one I&#8217;ve shown is the one where the mean initial HAM-D scores were high]. They&#8217;ve marked in <strong><font color=\"#00af01\">green<\/font><\/strong> the area they consider clinically significant [see their text]. Their conclusion:<\/div>\n<blockquote>\n<div align=\"justify\"><sup>&#8230; although differences in improvement increased at higher levels  of initial depression, there was a negative relation between severity  and the placebo response, whereas there was no difference between those  with relatively low and relatively high initial depression in their  response to drug. Thus, the increased benefit for extremely depressed  patients seems attributable to a decrease in responsiveness to placebo,  rather than an increase in responsiveness to medication.<\/sup><\/div>\n<\/blockquote>\n<div align=\"justify\">I interject here that these two studies reflect my own experience. I can&#8217;t personally validate the oft made claims that these medications are ineffective. My take clinically is that they are useful in people with significantly severe non-melancholic depression. Occasionally they help a lot, but more usually they only help some. And I agree with one of the implications of these studies, they seem to help keep people from spiraling downward. In milder depression, they have little to offer. The same profile sort of fits the older antidepressants &#8211; they just often carry an additional anticholinergic side effect burden that is poorly tolerated [To quote a friend who took them for a while, &quot;Hell, I&#8217;d rather be depressed than constipated!&quot;]. There&#8217;s something else about these studies that was unsaid. These <em>newer<\/em> antidepressants all do about the same thing. They may differ in side effect profiles or frequency of withdrawal syndromes, but neither my experience nor those graphs up there validate any of the hyped differences we heard so much in the Age of Patents. <\/div>\n<p><\/p>\n<div align=\"justify\"><img decoding=\"async\" align=\"right\" width=\"120\" hspace=\"4\" border=\"1\" src=\"http:\/\/3.bp.blogspot.com\/-OVSNymteeZU\/TZtHtd4UnPI\/AAAAAAAAIU4\/97f9xTPKw5M\/s400\/Back%2Bto%2Bthe%2BFuture%2BStorybook%2B%252801%2529.jpg\" \/><em>So, back to the future. I expect that the SSRI\/SNRI drugs will stay with us into the Age of the Generics &#8211; the short half-life drugs fading away because of their difficult withdrawal potential. They&#8217;ll be thought of as symptomatic drugs, useful in cases of severe depression, and we&#8217;ll be careful when we use them to watch for akathisia and suicidality early on. In the best of worlds, they&#8217;ll be used in the context of a comprehensive approach to mental health care rather than as the only treatment modality available. And hopefully, we&#8217;ll all be on the lookout for the less common melancholics and help them get the kind of treatment they deserve as Dr. Carroll suggests. Not so very different from how things were in 1979&#8230;<\/em><\/div>\n","protected":false},"excerpt":{"rendered":"<p>It hasn&#8217;t been the best of times, and we&#8217;re not far enough beyond to yet know if it has been the worst of times. All we really know is that it has been our times. I suppose that it&#8217;s always that way &#8211; one&#8217;s personal slice of history hasn&#8217;t really yet become history proper, it&#8217;s [&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-19710","post","type-post","status-publish","format-standard","hentry","category-politics"],"_links":{"self":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/19710","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=19710"}],"version-history":[{"count":43,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/19710\/revisions"}],"predecessor-version":[{"id":19804,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/19710\/revisions\/19804"}],"wp:attachment":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/media?parent=19710"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/categories?post=19710"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/tags?post=19710"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}