{"id":34997,"date":"2013-04-06T08:00:11","date_gmt":"2013-04-06T12:00:11","guid":{"rendered":"http:\/\/1boringoldman.com\/?p=34997"},"modified":"2013-04-06T08:13:51","modified_gmt":"2013-04-06T12:13:51","slug":"notwithstanding","status":"publish","type":"post","link":"https:\/\/1boringoldman.com\/index.php\/2013\/04\/06\/notwithstanding\/","title":{"rendered":"notwithstanding&#8230;"},"content":{"rendered":"\n<div align=\"justify\"><img decoding=\"async\" border=\"0\" align=\"right\" hspace=\"4\" height=\"150\" src=\"http:\/\/1boringoldman.com\/images\/forced-swim.gif\" \/>Some things take a moment to digest. This next bit from the story of anti-depressant drug development seems at first like something being made up, but that&#8217;s not the case. It&#8217;s called the <a target=\"_blank\" href=\"http:\/\/en.wikipedia.org\/wiki\/Behavioural_despair_test\">behavioral despair test<\/a>, the Porsolt, or the forced-swimming test [1977]:<\/div>\n<ul>\n<div align=\"justify\"><sup><strong>Animals are subjected to two trials during which they are forced to swim in an <span class=\"mw-redirect\">acrylic glass<\/span>  cylinder filled with water, and from which they cannot escape. The  first trial lasts 15 minutes. Then, after 24-hours, a second trial is  performed that lasts 5 minutes. The time that the test animal spends  without moving in the second trial is measured. This immobility time is  decreased by antidepressants.<\/strong><\/sup><\/div>\n<\/ul>\n<div align=\"justify\">Says Dr. Hyman [see <a href=\"http:\/\/1boringoldman.com\/index.php\/2013\/04\/05\/whither-the-crisis\/\" target=\"_blank\">whither the crisis&hellip;<\/a>]:<\/div>\n<blockquote>\n<div align=\"justify\"><sup><strong>Lacking molecular tools, pharmacologists working in psychiatry developed assays, mostly in laboratory rats, based on the effects of prototype drugs such as chlorpromazine, imipramine, and chlordiazepoxide [Librium] on animal behavior. For example, a rat placed in a beaker of cold water will swim for a time, but it will eventually stop swimming and begin to float. The antidepressant drug imipramine prolongs the period during which the rat attempts to swim. This forced swim assay was rationalized with anthropomorphic terms such as &ldquo;behavioral despair,&rdquo; but it was never shown to model human depression&#8230;<\/strong><\/sup><sup><strong> Despite some degree of surface plausibility&mdash;the forced swim result seemed to mimic learned helplessness, a putative model of depression&mdash;the mechanism by which imipramine causes continued swimming is still not known. Moreover, imipramine increases the duration of swimming with a single dose, whereas depressed human beings generally require several weeks of treatment before therapeutic effects emerge&#8230; From the very beginning, however, astute scientists predicted that this approach to drug development would result in the identification of only &ldquo;me too&rdquo; drugs. Unfortunately, during the last 50 years that concern has been fully borne out&#8230;<\/strong><\/sup> <\/div>\n<\/blockquote>\n<div align=\"justify\">This association of helplessness with depression has been around for a long time. Freud had seen anxiety as a biological signal of danger. Psychiatrist Edward Bibring extended that idea to depression which he saw as a signal of helplessness [1953]. Psychologist Martin Seligman came up with the idea of <em>learned helplessness<\/em> in the 1960s, popularized in a number of widely read books. Here&#8217;s an example set of results from the forced swimming test:<\/div>\n<div align=\"center\"><img loading=\"lazy\" decoding=\"async\" border=\"0\" width=\"448\" vspace=\"5\" height=\"149\" src=\"http:\/\/1boringoldman.com\/images\/forced-swim-1.gif\" \/><\/div>\n<blockquote>\n<div align=\"justify\"><sup><strong>Since the 1950s, scientists have worked to go beyond these assays and to create animal models of human depression, bipolar disorder, schizophrenia, and other psychiatric disorders. Relying mostly on laboratory rodents, they have used a range of tools from environmental stressors to the insertion of human disease risk genes into the brains or germ lines of mice. If we are to be clear-eyed about the results to date, we would have to conclude that none of these models have proven adequate&#8230;<\/strong><\/sup><\/div>\n<\/blockquote>\n<div align=\"justify\">Like the psychiatric literature, the research hopes are infused with <em><strong><font color=\"#200020\">future&middot;think<\/font><\/strong><\/em> and waiting for new technologies, new assays, new something that&#8217;s not here yet:<\/div>\n<blockquote>\n<div align=\"justify\"><sup><strong>As long as we guard against renewed self-deception about what constitutes meaningful advances, there is good reason to feel optimistic about the long-term future of translational psychiatry&mdash;despite its palpable scientific challenges. My optimism is based partly on the extraordinary vitality of neuroscience and perhaps, even more important, on the emergence of remarkable new tools and technologies to identify the genetic risk factors for psychiatric disorders, to investigate the circuitry of the human brain, and to replace current animal models that have failed to predict efficacious new drugs that act by novel mechanisms in the brain. New ideas are, of course, central to scientific progress, but new tools can open up unexpected worlds and thus undergird the formulation of truly novel hypotheses&#8230;<\/strong><\/sup><\/div>\n<\/blockquote>\n<div align=\"justify\">Animal models are central to biological and pharmaceutical research. And  it&#8217;s easy to see why they have such a hard time in psychiatric  research &#8211; they really don&#8217;t yet have much to work with. Their hopes for the  future seem to rest on psychiatric disorders that are genetically determined and as yet undiscovered <em>innovative<\/em> assay techniques:<\/div>\n<blockquote>\n<div><img decoding=\"async\" border=\"1\" align=\"left\" width=\"150\" vspace=\"2\" hspace=\"4\" src=\"http:\/\/1boringoldman.com\/images\/brain-chip.jpg\" \/><\/p>\n<div>\n<div align=\"justify\"><sup><strong>Our best hope is that the genetics will unfold over the next several years, due to the efforts of large international consortia that have formed to recruit and to study patients. As genetic clues accumulate, scientists are devising new ways to investigate their neurobiological functions and dysfunctions. One interesting development is to use stem cell technologies to complement the use of laboratory animals with human neurons engineered from skin cells of healthy subjects and from patients. <\/strong><\/sup><sup><strong>The leading approach is to take a small skin biopsy from the arms of volunteers and to transform skin fibroblasts into neural progenitors and into neurons. Genetic engineering can then be used to add risk-causing mutations to &ldquo;healthy&rdquo; neurons and to reverse risk mutations in patients&rsquo; neurons. But it is still early in this new field, and it is not yet possible to engineer the specific kinds of neurons implicated in schizophrenia by postmortem studies.<\/strong><\/sup><\/div>\n<\/div>\n<\/div>\n<\/blockquote>\n<div align=\"justify\">On one hand, I found Dr. Hyman&#8217;s article to be a fairly interesting tour through the state of the art in psychiatric drug development. It&#8217;s easy to see how his NIMH flowed into Insel&#8217;s NIMH &#8211; both dominated by a focus on finding ways to study drug treatment for psychiatric disorders &#8211; Translational Medicine, moving to bedside. It&#8217;s also easy to see the difficulty of their task. But on the other hand, I found it painfully monocular. First, it&#8217;s obvious that for him the central problem is the &quot;retreat&quot; of the pharmaceutical industry. At the risk of my being accused of being melodramatic, it has the feel of a piece written after being jilted by a lover. &quot;<em>How could he leave me? We were so good together. I need him!<\/em>&quot;:<\/div>\n<blockquote>\n<div align=\"justify\"><sup><strong>This retreat has occurred despite the fact that mental disorders are not only common worldwide, but also increasingly recognized by healthcare systems. There is, moreover, vast unmet medical need, meaning that many individuals with mental disorders remain symptomatic and often disabled despite existing treatments. For example, people suffering with the depressed phase of bipolar disorder often continue to experience severe symptoms even when they take multiple medications with serious side effects. For some significantly disabling conditions, such as the core social deficits of autism and the cognitive impairments of schizophrenia, there simply are no effective treatments. Because mental disorders are highly prevalent and our ability to treat them remains limited, these illnesses cause enormous societal burden. In aggregate, they are the world&rsquo;s leading cause of disability.<\/strong><\/sup><\/div>\n<p> <\/p>\n<div align=\"justify\"><sup><strong>In addition, this retreat has happened despite the fact that different classes of psychiatric drugs have been among the industry&rsquo;s most profitable products during the last several decades&mdash;and despite the fact that, according to Medco Health Solutions, one in five American adults now takes at least one psychiatric drug. Among the earliest commercial successes were the Valium-like benzodiazepines, used both as tranquilizers and as sleeping pills. These were followed by the Prozac-like selective serotonin reuptake inhibitor [SSRI] antidepressants. Most recently, &ldquo;second-generation&rdquo; antipsychotic drugs have been among the global revenue leaders for the pharmaceutical industry, serious side effects notwithstanding. That&rsquo;s why it&rsquo;s surprising that almost all industry research dollars are invested in cancer, metabolism, autoimmunity, and other disease areas&#8230;<\/strong><\/sup><\/div>\n<\/blockquote>\n<div align=\"justify\">&quot;<em>We gave him everything he wanted. How can he leave at a time like this?<\/em>&quot; The blurring of boundaries between academia and pharma&nbsp; and their goals couldn&#8217;t be more obvious &#8211; painfully obvious. And the second thing is that Dr. Hyman tells his story with no mention of the magnitude of corruption and deceit that this relationship has generated, or the epidemic of wrongful-doing pharma suits settled, or the entrepreneurialism among the academic KOLs. Do they think if they don&#8217;t talk about that stuff, it just won&#8217;t be there? <\/div>\n<p align=\"justify\">And this is really hard to hear him say, &quot;<em>&#8230; second-generation antipsychotic drugs have been among the global  revenue leaders for the pharmaceutical industry, <strong><font color=\"#200020\">serious side effects  notwithstanding<\/font><\/strong>.<\/em>&quot; There&#8217;s nothing about the minimized, ignored, or even denied <em><strong><font color=\"#200020\">serious side effects<\/font><\/strong><\/em> that fits with &quot;<em><strong><font color=\"#200020\">notwithstanding<\/font><\/strong><\/em>&quot;! I might add hidden from both patients and practicing doctors. If I were a patient who had those <em><strong><font color=\"#200020\">serious side effects <\/font><\/strong><\/em>reading this, I&#8217;d have trouble containing my rage, &quot;You knew about those <em><strong><font color=\"#200020\">serious side effects<\/font><\/strong><\/em>! and didn&#8217;t tell us!&quot;<\/p>\n<div align=\"justify\">There&#8217;s a disconnect here that&#8217;s hard to resolve. A lot of people are standing on their heads to right the wrongs of the past and to make sure they don&#8217;t happen again, and yet Drs. Insel, Hyman, and plenty of others are willing to stand on their heads to lure pharma back into the game, and seem willing to do almost anything to facilitate their return. For this latter group, the crisis is that pharma is pulling out, instead of the crisis of integrity that&#8217;s so painfully clear. Perhaps holding up the academic end of this bargain along the way, including not signing on to papers from the spirit world, might have averted this crisis all together&#8230;<\/div>\n","protected":false},"excerpt":{"rendered":"<p>Some things take a moment to digest. This next bit from the story of anti-depressant drug development seems at first like something being made up, but that&#8217;s not the case. It&#8217;s called the behavioral despair test, the Porsolt, or the forced-swimming test [1977]: Animals are subjected to two trials during which they are forced to [&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-34997","post","type-post","status-publish","format-standard","hentry","category-politics"],"_links":{"self":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/34997","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=34997"}],"version-history":[{"count":35,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/34997\/revisions"}],"predecessor-version":[{"id":35027,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/34997\/revisions\/35027"}],"wp:attachment":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/media?parent=34997"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/categories?post=34997"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/tags?post=34997"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}