{"id":35423,"date":"2013-04-16T19:28:47","date_gmt":"2013-04-16T23:28:47","guid":{"rendered":"http:\/\/1boringoldman.com\/?p=35423"},"modified":"2013-04-16T19:54:08","modified_gmt":"2013-04-16T23:54:08","slug":"a-fascinating-tale","status":"publish","type":"post","link":"https:\/\/1boringoldman.com\/index.php\/2013\/04\/16\/a-fascinating-tale\/","title":{"rendered":"a fascinating tale&#8230;"},"content":{"rendered":"\n<div align=\"justify\"><a target=\"_blank\" href=\"http:\/\/davidhealy.org\/\">Dr. David Healy<\/a> has just published the fourth installment [4\/6] of his series on clinical trials:<\/div>\n<ul><sup><strong>                  <\/p>\n<li><a target=\"_blank\" href=\"http:\/\/davidhealy.org\/not-so-bad-pharma\/\">Not So Bad Pharma<\/a> &#8211; March 28<\/li>\n<li><a target=\"_blank\" href=\"http:\/\/davidhealy.org\/april-fool-in-harlow-anecdote-fishing-in-harlow\/\">April Fool in Harlow: Anecdote Fishing in Harlow<\/a> &#8211; April 1<\/li>\n<li><a target=\"_blank\" href=\"http:\/\/davidhealy.org\/the-tragedy-of-lou-lasagna\/\">The Tragedy of Lou Lasagna<\/a> &#8211; April 9<\/li>\n<li><a target=\"_blank\" href=\"http:\/\/davidhealy.org\/the-empire-of-humbug-bad-pharma\/\">The Empire of Humbug: Bad Pharma<\/a> &#8211; April 15<\/li>\n<p>                  <\/strong><\/sup><\/ul>\n<div align=\"justify\">Most of us are appalled with the way clinical trials have been manipulated by the pharmaceutical industry and complicit psychiatrists to further the economic interests of their company&#8217;s products and are backing efforts at reform. Dr. Healy&#8217;s concerns go further, questioning the primacy of clinical trials altogether. In this installment, he takes us back almost 60 years to the earliest days of double-blind <strong><font color=\"#200020\">randomized<\/font><\/strong> placebo-controlled <strong><font color=\"#200020\">clinical trials<\/font><\/strong> [RCTs], and he has a fascinating tale to tell. How do I know it&#8217;s a fascinating tale? It&#8217;s because in this post, I&#8217;m only going to get through the first several paragraphs, having found enough there to keep me occupied for a while:<\/div>\n<blockquote>\n<div align=\"center\"><a target=\"_blank\" href=\"http:\/\/davidhealy.org\/the-empire-of-humbug-bad-pharma\/\"><strong><font color=\"#200020\">The Empire of Humbug: Bad Pharma<\/font><\/strong><\/a><br \/>          by David Healy<br \/>          April 15, 2013<\/div>\n<p><strong><font color=\"#200020\">The first RCT<\/font><\/strong><\/p>\n<p align=\"justify\"><sup><strong>In 1956, two of the creators  of the modern RCT, Lou Lasagna and Michael Shepherd, met.&nbsp;The  randomization in randomized placebo controlled trials came from Bradford  Hill in Britain and placebo controls from Beecher, Gold and Lasagna in  the US.&nbsp;In 1956, Michael Shepherd, Bradford-Hill&rsquo;s representative in all  things psychiatric, came on sabbatical to stay with Lasagna at  Hopkins&rsquo;.<\/strong><\/sup><\/p>\n<p align=\"justify\"><sup><strong>In 1947 Bradford-Hill ran the first randomized trial.&nbsp;In 1955,  Shepherd added in Lasagna and Beecher&rsquo;s placebo to the original  randomized design and published in the Lancet the first ever RCT of the  type used today in drug trials submitted to FDA for regulatory  approval.&nbsp;His trial compared reserpine to placebo in a group of  outpatients with mixed anxiety and depression &ndash; similar patients to  those later given Prozac and other SSRIs.&nbsp;Reserpine was better than  Prozac and other SSRIs later were, and indeed did better than imipramine  did a few years later in a trial run by Lasagna.&nbsp;There was no sign in  Shepherd&rsquo;s trial of the suicide hazard for which reserpine is now best  remembered.<\/strong><\/sup><\/p>\n<div align=\"justify\"><sup><strong>The two articles that immediately preceded Shepherd&rsquo;s study in this  issue of the Lancet described hypertensive patients being treated with  reserpine who became suicidal. When later asked why his trial had almost  no impact, Shepherd&rsquo;s off-the-cuff response was that doctors were not  used to seeing results being presented in this way.&nbsp;But there was in  fact no commercial incentive for any company to use his results to  relegate the accounts of suicide on reserpine to the status of  anecdotes&#8230;<\/strong><\/sup><\/div>\n<p align=\"justify\"> <sup><strong>The two articles that immediately preceded Shepherd&rsquo;s study in this  issue of the Lancet described hypertensive patients being treated with  reserpine who became suicidal. When later asked why his trial had almost  no impact, Shepherd&rsquo;s off-the-cuff response was that doctors were not  used to seeing results being presented in this way.&nbsp;But there was in  fact no commercial incentive for any company to use his results to  relegate the accounts of suicide on reserpine to the status of  anecdotes&#8230;<\/strong><\/sup><\/p>\n<\/blockquote>\n<div align=\"justify\">From 1967 to 1971, I was a house officer in Internal Medicine in a place where Malignant Hypertension was prevalent and Reserpine was a mainstay of treatment, with reservations. So that couple of paragraphs caught my attention. By the time I came along, we only used Reserpine for acute management of life-threatening Malignant Hypertension <em><strong><font color=\"#200020\">because<\/font><\/strong><\/em> the drug was known to cause severe depressions. In fact, somewhere along the way, I even recall a Medicine Grand Rounds on Reserpine as a biological model of Depression for etiological research:<\/div>\n<div align=\"center\"><img loading=\"lazy\" decoding=\"async\" border=\"0\" width=\"300\" height=\"206\" src=\"http:\/\/1boringoldman.com\/images\/healy-2.gif\" \/><\/div>\n<div align=\"justify\">This is a snippet from <strong><font color=\"#200020\">The Lancet<\/font><\/strong>&#8216;s table of contents on July 16, 1955. The highlighted paper by Davies and Shepherd is, as Dr. Healy tells us, the first RTC ever published &#8211; a paper on a six week trial of Reserpine in psychiatric conditions. It looks something like the modern version: randomization, placebo controlled, drop-outs along the way. The rating scale was physician rated at six weeks [the subjects answered question A]. It was pretty subjective by modern standards:<\/div>\n<div align=\"center\"><img loading=\"lazy\" decoding=\"async\" border=\"0\" width=\"500\" vspace=\"5\" height=\"174\" src=\"http:\/\/1boringoldman.com\/images\/healy-3.gif\" \/><\/div>\n<div align=\"justify\">The patients studied had a variety of psychiatric <em>reactions<\/em> [as they were called in the first DSM in 1952]:<\/div>\n<div align=\"center\"><img decoding=\"async\" border=\"0\" width=\"300\" vspace=\"5\" src=\"http:\/\/1boringoldman.com\/images\/healy-5.gif\" \/><\/div>\n<div align=\"justify\">I graphed a few of the physician rated outcomes:<\/div>\n<div align=\"center\"><img loading=\"lazy\" decoding=\"async\" border=\"0\" width=\"500\" vspace=\"5\" height=\"138\" src=\"http:\/\/1boringoldman.com\/images\/healy-4.gif\" \/><\/div>\n<div align=\"justify\">So here in the first ever trial, there was some placebo effect and some efficacy. They had this to say about the side effects:<\/div>\n<div align=\"justify\">\n<blockquote>\n<div><sup><strong>Separate mention should be made of the side-effects among those patients who completed the six-week trial. These were all attributed by the patients to the substance which they were taking. Among the patients on reserpine, 3 complained of nasal stuffiness, 4 of what was described as &quot; shivering,&quot; and 2 of giddiness and dizziness ; 1 commented on his large appetite, 1 on increased libido, and 1 of many somatic anxiety symptoms. Of the patients on placebo, 3 complained of fatigue, and 1 felt elated for the first day or two : the more dramatic side-effects displayed by 1 of the patients who did not continue with his tablets have already been mentioned.<\/strong><\/sup><\/div>\n<\/blockquote><\/div>\n<div align=\"justify\">Had I given Reserpine to an outpatient for long term use for anything during my years in Internal Medicine Residency, I would have likely found myself in some higher-up&#8217;s office getting a lecture about the dangers of doing that very thing and being handed a stack of articles about the topic to present at the next journal club. It was a big &quot;no-no.&quot; But this 1955 article came a decade and a half before my time, at the time when people were learning. <strong><font color=\"#200020\">It is a matter of fortuitous irony that two articles where that learning about Reserpine&#8217;s adverse effects was occurring immediately preceded this article on the psychiatric uses of Reserpine<\/font><\/strong> [the first RCT]. Here&#8217;s are a couple of quotes from those two articles:<\/div>\n<div align=\"justify\">\n<blockquote>\n<div><sup><strong>Unfortunately about 10% of our patients who received reserpine, either alone or in combination with pentolinium, have experienced substantial degrees of mental depression and about 5% have required psychiatric treatment. Mild degrees of depression are even more frequent. Some patients on reserpine also complain of lassitude and sleepiness during the day and of disturbed sleep with nightmares at night.<\/strong><\/sup><\/div>\n<\/blockquote><\/div>\n<blockquote>\n<div align=\"justify\"><sup><strong>The very encouraging reports of the effect on hyper-tension of the rauwolfia alkaloids, and of a combination of reserpine and pentolinium, encouraged me to use this form of treatment where possible. Until recently I thought that an almost ideal treatment had been achieved, but when the third case of melancholia in a severe hypertensive treated with this combination was observed, I became doubtful of the safety of the method.<\/strong><\/sup><\/div>\n<div align=\"center\"><img loading=\"lazy\" decoding=\"async\" border=\"0\" width=\"66\" height=\"18\" src=\"http:\/\/1boringoldman.com\/images\/snip.gif\" \/><\/div>\n<div align=\"justify\"><sup><strong>In 133 patients with hypertension, treated as private patients in a general practice over a period of thirty months, there was a group of severe hypertensives who benefited considerably from combined oral reserpine and pentolinium. No less than 4 patients out of 44 who received reserpine alone or in combination had severe mental depression amounting in 3 cases to melancholia with delusions.<\/strong><\/sup><\/div>\n<\/blockquote>\n<div>My apologies to Dr. Healy for going off on my side trip. I&#8217;ll return to his main thread later. Here in 1955 at the dawn of the clinical trial era, we have a glimpse of how things used to work and a peek into one of the problems of clinical trials [even well conducted clinical trials] that continues to plague us even today. First, how things worked in the past. <\/div>\n<p align=\"justify\">Malignant hypertension is a killer. By the time the patient presents for treatment, there are usually signs of clouded consciousness and a intracerebral bleed [stroke] is just around the corner. It is common in the African American population that came to the large City Hospital in Memphis where I trained. If you needed to get the blood pressure down in a hurry, Resperpine was a first-line treatment. It had been introduced in 1952. After the crisis had passed, the next order of business was to change to another drug for maintenance, as the incidence of depressive illness on long term Reserpine was high [higher in my memory than reported here]. So here, even as it was being studied as an antidepressant\/anxiolytic, we have two reports of its capacity to cause depression &#8211; one from a New Zealand research center trying an alternative drug and one from a practitioner in Australia who had noticed some hypertensive patients who became profoundly depressed on the drug and reviewed his practice. That&#8217;s how it used to work. A practitioner noticed something, looked into it, and let the rest of us in the world of medicine know with a report like this one in the Lancet. Both articles report that Resperpine is a good antihypertensive. Both give an approximate 10% incidence of depression.<\/p>\n<p align=\"justify\">And now for the problem that haunts us to the present. The six week clinical trial of Reserpine showed that it was useful in a number of psychiatric dimensions, proven by a statistically significant double-blind <strong><font color=\"#200020\">randomized<\/font><\/strong> placebo-controlled <strong><font color=\"#200020\">clinical trial<\/font><\/strong> &#8211; the first in history. And that&#8217;s correct. Reserpine has both antipsychotic and antidepressant properties. It was used as an early treatment for psychosis before the introduction of Thorazine a few years later. Unfortunately, in the long term, it can cause depressions indistinguishable from naturally occurring psychotic depressions &#8211; big ones. As we well know, generalizing from the brief clinical trials now used for approving drugs misses a lot of what can happen with prolonged use. It&#8217;s a lesson taught repeatedly with the antidepressants and antipsychotics well into the modern era.<\/p>\n<div align=\"justify\">Dr. Healy&#8217;s tale remain fascinating, open on my desktop, and awaits further exploration&#8230;<\/div>\n","protected":false},"excerpt":{"rendered":"<p>Dr. David Healy has just published the fourth installment [4\/6] of his series on clinical trials: Not So Bad Pharma &#8211; March 28 April Fool in Harlow: Anecdote Fishing in Harlow &#8211; April 1 The Tragedy of Lou Lasagna &#8211; April 9 The Empire of Humbug: Bad Pharma &#8211; April 15 Most of us are [&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-35423","post","type-post","status-publish","format-standard","hentry","category-politics"],"_links":{"self":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/35423","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=35423"}],"version-history":[{"count":19,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/35423\/revisions"}],"predecessor-version":[{"id":35442,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/35423\/revisions\/35442"}],"wp:attachment":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/media?parent=35423"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/categories?post=35423"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/tags?post=35423"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}