{"id":63401,"date":"2016-02-12T21:28:18","date_gmt":"2016-02-13T02:28:18","guid":{"rendered":"http:\/\/1boringoldman.com\/?p=63401"},"modified":"2016-02-12T21:51:41","modified_gmt":"2016-02-13T02:51:41","slug":"pipe-dreams","status":"publish","type":"post","link":"https:\/\/1boringoldman.com\/index.php\/2016\/02\/12\/pipe-dreams\/","title":{"rendered":"pipe dreams…"},"content":{"rendered":"
I suppose that with the drought in the PHARMA CNS pipeline, it should have been predictable that thoughts would turn towards the known feel-good drugs<\/font><\/em> [drugs in the street-sense as opposed to medications]. In October, we heard about Special K<\/font><\/em>, a club drug, looking to be reborn as a antidepressant …<\/div>\n
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Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression<\/a><\/div>\n
by D. Jeffrey Newport, Linda L. Carpenter<\/font><\/strong>, William M. McDonald<\/font><\/strong>, James B. Potash<\/font><\/strong>, Mauricio Tohen<\/font><\/strong>, and Charles B. Nemeroff<\/font><\/strong>, The APA Council of Research Task Force on Novel Biomarkers and Treatments <\/div>\n
American Journal of Psychiatry<\/font><\/strong>. 2015 172:950–966.<\/div>\n

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… Other NMDA antagonists failed to consistently demonstrate efficacy; however, two partial agonists at the NMDA coagonist site, D-cycloserine and rapastinel, significantly reduced depressive symptoms without psychotomimetic or dissociative effects.<\/div>\n
Conclusions<\/font><\/strong><\/u>: The antidepressant efficacy of ketamine, and perhaps D-cycloserine and rapastinel, holds promise for future glutamate-modulating strategies<\/font><\/strong><\/em>; however, the ineffectiveness of other NMDA antagonists suggests that any forthcoming advances will depend on improving our understanding of ketamine’s mechanism of action. The fleeting nature of ketamine’s therapeutic benefit, coupled with its potential for abuse and neurotoxicity, suggest that its use in the clinical setting warrants caution.<\/div>\n<\/blockquote>\n
… with emphasis on a couple of derivative drugs that weren’t so "clubby<\/font><\/em>" [that also have a significant commercial potential and obvious author Conflicts of Interest – see a touch of paralysis…<\/a> and infomercials…<\/a>]. Now, there’s a lot of excitement around exploiting an old standby – the opiate receptors. Interestingly, it comes at a time of an epidemic of opiate abuse – traffic coming straight from the poppies<\/font><\/em> and from the pharmaceutical pain pills<\/font><\/em>. With my blog about Dr. Nemeroff et al’s Ketamine article, I spread the COI declarations throughout the text. Those connections are here too and I’m going to stick them in at the end. But to summarize them, the clinical trial from this month’s AJP is industry financed, has four academic AKA known KOL authors all with connections with the drug manufacturer, and seven authors who are actually full time employees.<\/div>\n
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Opioid Modulation With Buprenorphine\/Samidorphan as Adjunctive Treatment for Inadequate Response to Antidepressants: A Randomized Double-Blind Placebo-Controlled Trial<\/a><\/div>\n
by Maurizio Fava, M.D., Asli Memisoglu, Sc.D., Michael E. Thase, M.D., J. Alexander Bodkin, M.D., Madhukar H. Trivedi, M.D., Marc de Somer, M.D., M.P.H., Yangchun Du, Ph.D., Richard Leigh-Pemberton, M.D., Lauren DiPetrillo, Ph.D., Bernard Silverman, M.D., Elliot Ehrich, M.D.<\/div>\n
American Journal of Psychiatry<\/font><\/strong>. Published online: February 12, 2016<\/div>\n

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Objective<\/font><\/strong><\/em>: Major depressive disorder has been associated with dysregulation of the endogenous opioid system. The authors sought to determine whether opioid modulation achieved through administration of ALKS 5461, a combination of an m- and k-opioid partial agonist, buprenorphine, and an opioid antagonist, samidorphan, would exhibit antidepressant activity in patients with major depression.<\/div>\n
Method<\/font><\/strong><\/em>: A multicenter, randomized, double-blind, placebo- controlled, two-stage sequenti al parallel comparison design study was conducted in adults with major depression who had an inadequate response to one or two courses of antidepressant treatment. Participants were randomly assigned to receive adjunctive treatment with 2mg\/2mg of buprenorphine\/samidorphan [the 2\/2 dosage group], 8mg\/8mg of buprenorphine\/samidorphan [the 8\/8 dosage group], or placebo. Antidepressant effect was measured based on change from baseline to the end of 4 weeks of treatment on the 17-item Hamilton Depression Rating Scale [HAM-D], the Montgomery-Åsberg Depression Rating Scale [MADRS], and the Clinical Global Impressions severity scale [CGI-S].<\/div>\n
Results<\/font><\/strong><\/em>: Compared with the placebo group, there were significantly greater improvements in the 2\/2 dosage group across the three depression outcome measures [HAM-D: -2.8, 95% CI= -5.1, -0.6; MADRS: -4.9, 95%CI= -8.2, -1.6; CGI-S: -0.5, 95% CI= -0.9, -0.1]. There was also evidence of improvement in the 8\/8 dosage group, although it did not achieve statistical significance. Overall, the buprenorphine\/samidorphan combinations were well tolerated, and there was no evidence of opioid withdrawal on treatment discontinuation.<\/div>\n
Conclusions<\/font><\/strong><\/em>: The buprenorphine\/samidorphan combination is a novel and promising candidate for treatment of major depressive disorder in patients who have an inadequate response to standard antidepressants.<\/div>\n<\/blockquote>\n
Buprenorphine<\/a>  along with Naloxone<\/a> are the ingredients in Suboxone<\/a>® – the sublingual film used in the treament of Opioid addiction. The Buprenorphine is a morphine agonist similar to Methadone<\/a>. The Naloxone is there to prevent IV use as it will throw users into withdrawal [not necessarily true in people not already addicted]. In the combination described in this paper, Buprenorphine is combined with Samidorphan<\/a>, another narcotic antagonist. This combination showed promise in treating depression i<\/a>n its early phase trials, but then failed in two later trials reported just last month [Alkermes Depression Drug Disappoints in Trials<\/a>, Alkermes shares plunge after drug misses trial goals<\/a>, Alkermes depression drug fails, shares plunge<\/a>, Alkermes Falls Most Since 2002 as Depression Drug Trials Fail<\/a>]. And the closely watched stock tanked in a day.<\/div>\n

The study above, reported in the American Journal of Psychiatry<\/font>  today was Received: July 15, 2015<\/font> and Accepted: November 30, 2015<\/font>. It was one of those earlier studies that generated all that excitement on Wall Street. It was a "Two-Stage Sequential Parallel Comparison Design Study<\/font>" – it’s something of a crossover design but too complex to explain without reproducing the whole article. The same for the analysis. Speaking of complex, they had a fancy way of evaluating their crossover data that included this $50 formula:<\/p>\n

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[I sure didn’t get it]. In the end, they reported a significant difference for the lower but not the higher dose of their drug combo [HAM-D p=0.02, MADRS p=0.005, CGI p=0.03]. Of note, there were no significant differences in the patient self rating scales<\/font> [Inventory of Depressive Symptomatology Self-Report, the Sheehan Disability Scale, or the SF-12]. <\/p>\n

It’s hard for me to imagine that they’ll ever succeed in engineering an opiate that has some therapeutic effect without the obvious problem of abuse and addiction – the kind that practitioners already deal with every day. I literally surrendered the narcotic<\/font><\/em> part of my narcotic license in order to be able to say "I can’t prescribe pain pills." I was just so weary from being hit on for narcotics. And frankly, it feels a lot like the deepest theory herein is to over-ride depressive affect with the euphoric effect of opium. That experiment has already gone on for centuries without coming to any good end.<\/p>\n

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AUTHOR AND ARTICLE INFORMATION<\/font><\/strong><\/em><\/div>\n
From the Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston; Alkermes<\/font><\/em><\/strong>, Inc., Waltham, Mass.; the Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia; McLean Hospital, Belmont, Mass.; and the Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas. Address correspondence to Dr. Fava [mfava@partners.org].<\/div>\n
Presented at the 53rd annual meeting of the New Clinical Drug Evaluation Unit, Hollywood, Fla., May 28 – 31, 2013.<\/div>\n
Supported by <\/font><\/strong>Alkermes<\/font><\/strong><\/em>, Inc., Waltham, Mass. The authors thank Mark S. Todtenkopf, Ph.D., for assistance in the preparation of the manuscript; the ALKS 5461 investigator study group; and Richard S. Perry, Pharm.D., for editorial assistance in the preparation of the manuscript, which was supported by Alkermes<\/font><\/strong><\/em>, Inc.<\/div>\n
ClinicalTrials.gov identifier<\/font><\/strong><\/em>: NCT01500200<\/a>.<\/div>\n
Dr. Fava<\/font><\/strong><\/em> has received research support from and\/or served as an adviser or consultant to Acadia, Alkermes<\/font><\/strong><\/em>, AstraZeneca, Avanir, AXSOME Ther- apeutics, Biogen, Bristol-Myers Squibb, Cerecor, Dinippon Sumitomo Pharma, Eli Lilly, EnVivo, Euthymics Bioscience, Forest Pharmaceuticals, FORUM Pharmaceuticals, GenOmind, GlaxoSmithKline, Intracellular, Janssen R&D, Johnson & Johnson Pharmaceutical Research and De- velopment, Lundbeck, Merck, Methylation Sciences, MSI Methylation Sciences, the National Center for Complementary and Alternative Med- icine, the National Coordinating Center for Integrative Medicine, NIDA, NIMH, Naurex, Nestle Health Sciences, Neuralstem, Novartis AG, Nutrition 21, Osmotica, Otsuka Pharmaceuticals, PamLab, Pfizer, PharmoRx Therapeutics, Photothera, PPD, Puretech Ventures, PsychoGenics, RCT Logic [formerly Clinical Trials Solutions], Reckitt Benckiser, Ridge Diagnostics, Roche Pharmaceuticals, Sanofi-Aventis, Servier Laboratories, the Stanley Medical Research Institute, Sunovion, Taisho, Takeda, Tal Medical, and VistaGen; he has had speaking or publishing roles for the American Society of Clinical Psychopharmacology, Belvoir Media Group, CME Institute\/Physicians Postgraduate Press, and MGH Psychiatry Academy; he has equity holdings in Compellis and PsyBrain; he is named on patents for sequential parallel comparison design, licensed by MGH to Pharma- ceutical Product Development and a patent application for a combination of ketamine plus scopolamine in major depressive disorder, licensed by MGH to Biohaven; and he is a copyright holder for the MGH Cognitive and Physical Functioning Questionnaire, the Sexual Functioning Inventory, the Antidepressant Treatment Response Questionnaire, Discontinuation-Emergent Signs and Symptoms, the Symptoms of Depression Questionnaire, and SAFER and has publications with Lippincott Williams & Wilkins, Wolkers Kluwer, and World Scientific Publishing.<\/div>\n
Dr. Thase<\/font><\/strong><\/em> has served as an adviser or consultant to Alkermes<\/font><\/strong><\/em>, Allergan [includes Forest Laboratories and Naurex], Avanir, AstraZeneca, Bristol-Myers Squibb, Cerecor, Eli Lilly, Lundbeck, Johnson & Johnson [includes Ortho-McNeil and Janssen], MedAvante, Merck [includes Schering-Plough and Organon], Nestl\u00e9 [includes Pamlab], Neuronetics, Novartis, Otsuka, Pfizer [includes Wyeth Ayerst], Roche, Sunovion, and Takeda; he has received grant support from Agency for Healthcare Research and Quality, Alkermes, Avenir, Eli Lilly, Forest, Johnson & Johnson, NIMH, Otsuka, Phar- maNeuroboost, and Roche; he has equity holdings in MedAvante and receives royalties from American Psychiatric Foundation, Guilford Publications, Herald House, and W.W. Norton; his spouse is employed by Peloton Advantage, which does business with Pfizer. <\/div>\n
Dr. Bodkin<\/font><\/strong><\/em> has received payment for participation in advisory panel meetings related to the investigation of ALKS 5461<\/font><\/strong><\/em> as a potential treatment for psychiatric disorders and has served as a consultant and received research support from Bristol-Myers Squibb, Otsuka, and CeNeRx, served as a consultant to MyTomorrows, has received research support from Shire, and has received grant support from NIH\/NIMH.<\/div>\n
Dr. Trivedi<\/font><\/strong><\/em> has served as a consultant to or received fees from Alkermes<\/font><\/strong><\/em>, AstraZeneca, Bristol-Myers Squibb, Cerecor, Eli Lilly, Forest, Johnson & Johnson, Lundbeck, Merck, Naurex, Neuronetics, Otsuka, Pamlab, Pfizer, Rexahn, Roche, and Shire and has served on a scientific advisory board for Rexahn; he has received research support from NIMH and NIDA. <\/div>\n
Drs. Memisoglu, de Somer, Du, Leigh-Pemberton, DiPetrillo, Silverman, <\/font><\/strong><\/em>and Ehrich<\/font><\/strong><\/em> are or have been full-time employees of Alkermes<\/font><\/strong><\/em>, Inc., and have stock options.<\/div>\n<\/blockquote>\n
 <\/div>\n","protected":false},"excerpt":{"rendered":"

I suppose that with the drought in the PHARMA CNS pipeline, it should have been predictable that thoughts would turn towards the known feel-good drugs [drugs in the street-sense as opposed to medications]. In October, we heard about Special K, a club drug, looking to be reborn as a antidepressant … Ketamine and Other NMDA […]<\/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":[5],"tags":[],"class_list":["post-63401","post","type-post","status-publish","format-standard","hentry","category-opinion"],"_links":{"self":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/63401","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=63401"}],"version-history":[{"count":42,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/63401\/revisions"}],"predecessor-version":[{"id":63443,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/63401\/revisions\/63443"}],"wp:attachment":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/media?parent=63401"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/categories?post=63401"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/tags?post=63401"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}