{"id":67651,"date":"2016-09-08T23:55:04","date_gmt":"2016-09-09T03:55:04","guid":{"rendered":"http:\/\/1boringoldman.com\/?p=67651"},"modified":"2016-09-09T05:28:10","modified_gmt":"2016-09-09T09:28:10","slug":"of-mice-and-men-2","status":"publish","type":"post","link":"https:\/\/1boringoldman.com\/index.php\/2016\/09\/08\/of-mice-and-men-2\/","title":{"rendered":"of mice and men&#8230;"},"content":{"rendered":"\n<p align=\"justify\" class=\"small\">Nosing around about <font color=\"#200020\">Ketamine<\/font>, I ran across this draft that I never posted from 2&frac12; years ago:<\/p>\n<table width=\"95%\" cellspacing=\"0\" cellpadding=\"0\" border=\"0\" align=\"center\">\n<tr>\n<td>\n<div align=\"justify\"><sup><strong><em><font color=\"#200020\">from<\/font><\/em> <font color=\"#200020\">February 19, 2014:<\/font><\/strong> <a target=\"_blank\" href=\"http:\/\/blogs.discovermagazine.com\/neuroskeptic\/2014\/02\/08\/depression-ketamine-struck-gold\/#.UvhTioWmWyg\">Neuroskeptic<\/a> has an interesting thing going trying to figure out if the effect on depressed people from Ketamine is because Ketamine is a pharmacologic antidepressant, or, to put it in my own worlds, does getting <strike>stoned<\/strike> <strike>ripped<\/strike> <strike>dissociated<\/strike> feeling something psychodelic help depressed people? He starts by&nbsp; discounting studies that compare Ketamine to Placebo since Ketamine is obviously psychoactive and a Placebo isn&#8217;t. Then he moves to a study that compared Ketamine to a Benzodiazepine &#8211; another psychoactive drug. That&#8217;s difficult because though Benzodiazepines are psychoactive, they&#8217;re sedatives. Ketamine is something else. He mentions <a href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/24480515\" target=\"_blank\">a study<\/a> that&#8217;s not in depressed people, but it&#8217;s pretty interesting. The subjects were Cocaine a<\/sup><sup>ddicts who wanted to quit. They compared Ketamine to a benzodiazepine too. Here are the results of the questions they asked:<\/sup><\/div>\n<div align=\"center\"><img decoding=\"async\" width=\"450\" vspace=\"7\" border=\"1\" src=\"http:\/\/blogs.discovermagazine.com\/neuroskeptic\/files\/2014\/02\/dakwar.png\" \/><\/div>\n<div align=\"justify\"><sup>T<\/sup><sup>hat&#8217;s going to be a hard comparator to find! And it begs the question if it&#8217;s helping because it gets the depressed &quot;out of themselves.&quot; If you&#8217;ve worked an ER where people have been brought having taken Ketamine, it&#8217;s just hard to imagine using it as a therapeutic agent. They are <u>way<\/u> &quot;out of themselves!&quot; So here&#8217;s what Neuroskeptic said:<\/sup><\/div>\n<ul>\n<div align=\"justify\"><strong><em><font color=\"#200020\"><img decoding=\"async\" hspace=\"4\" height=\"50\" border=\"0\" align=\"left\" src=\"http:\/\/1boringoldman.com\/images\/neuroskeptic.gif\" \/><\/font><font color=\"#660033\"><sup>In summary I think the question is still very much open whether  ketamine&rsquo;s antidepressant effects are &lsquo;psychological&rsquo; or &lsquo;physiological&rsquo;  in origin. I&rsquo;m genuinely agnostic on the issue; I would love to know  the answer, but at present we don&rsquo;t have it.<\/sup><\/font><\/em><\/strong><\/div>\n<\/ul>\n<div align=\"justify\"><sup>I&#8217;m going to vote &#8216;psychological&#8217;&#8230;<\/sup><\/div>\n<\/td>\n<\/tr>\n<\/table>\n<p align=\"justify\" class=\"small\">I&#8217;m obviously not quite so <font color=\"#200020\">agnostic<\/font> as <font color=\"#200020\">Neuroskeptic<\/font> when it comes to Ketamine, but I&#8217;m open to being born&middot;again given something really solid. The question remains, &quot;Is the manifest improvement in depressive symptoms following the initial psychodelic experience <em><font color=\"#200020\">&lsquo;psychological&rsquo; or &lsquo;physiological&rsquo;?<\/font><\/em>&quot; and I have to concede that I don&#8217;t really know the answer. I certainly can&#8217;t argue that there&#8217;s not an effect [this <font color=\"#200020\">Janssen<\/font> article from the recent <strong><font color=\"#004400\">AJP<\/font><\/strong>]:<\/p>\n<blockquote>\n<div align=\"center\" class=\"big\"><a target=\"_blank\" href=\"http:\/\/ajp.psychiatryonline.org\/doi\/abs\/10.1176\/appi.ajp.2016.16010037?journalCode=ajp\">A Double-Blind, Randomized, Placebo-Controlled, Dose-Frequency Study of Intravenous Ketamine in Patients With Treatment-Resistant Depression<\/a><\/div>\n<div align=\"center\" class=\"middle\">by <strong><font color=\"#0033ff\">Jaskaran B. Singh<\/font><\/strong>,<strong><font color=\"#0033ff\"> Maggie Fedgchin<\/font><\/strong>,<strong><font color=\"#0033ff\"> Ella J. Daly<\/font><\/strong>,<strong><font color=\"#0033ff\"> Peter De Boer<\/font><\/strong>, <strong><font color=\"#0033ff\">Kimberly Cooper<\/font><\/strong>, <strong><font color=\"#0033ff\">Pilar Lim<\/font><\/strong>, <strong><font color=\"#660033\">Christine Pinter<\/font><\/strong>,<strong><font color=\"#660033\"> James W. Murrough<\/font><\/strong>,<strong><font color=\"#660033\"> Gerard Sanacora<\/font><\/strong>,<strong><font color=\"#660033\"> Richard C. Shelton<\/font><\/strong>,<strong><font color=\"#660033\"> Benji Kurian<\/font><\/strong>,<strong><font color=\"#660033\"> Andrew Winokur<\/font><\/strong>,<strong><font color=\"#660033\"> Maurizio Fava<\/font><\/strong>, <strong><font color=\"#0033ff\">Husseini Manji<\/font><\/strong>, <strong><font color=\"#0033ff\">Wayne C. Drevets<\/font><\/strong>, and <strong><font color=\"#0033ff\">Luc Van Nueten<\/font><\/strong><\/div>\n<div align=\"center\" class=\"middle\"><strong><font color=\"#200020\">&laquo;<\/font><font color=\"#0033ff\">Janssen Employees<\/font><\/strong>, <strong><font color=\"#660033\">Janssen COI<\/font><font color=\"#200020\">&raquo;<\/font><\/strong>    <\/div>\n<div align=\"center\" class=\"middle\"><strong><font color=\"#004400\">American Journal of Psychiatry<\/font><\/strong>. 2016 173:816&ndash;826.<\/div>\n<p>                                             <\/p>\n<div align=\"justify\"><em><strong><font color=\"#200020\">Objective<\/font><\/strong><\/em>: Ketamine, an N-methyl-D-aspartate glutamate receptor antagonist, has demonstrated a rapid-onset antidepressant effect in patients with treatment-resistant depression. This study evaluated the efficacy of twice- and thrice-weekly intravenous administration of ketamine in sustaining initial antidepressant effects in patients with treatment-resistant depression.<\/div>\n<div align=\"justify\"><em><strong><font color=\"#200020\">Method<\/font><\/strong><\/em>: In a multicenter, double-blind study, adults [ages 18&ndash;64 years] with treatment-resistant depression were randomized to receive either intravenous ketamine [0.5 mg\/kg of body weight] or intravenous placebo, administered over 40 minutes, either two or three times weekly, for up to 4 weeks. Patients who discontinued double-blind treatment after at least 2 weeks for lack of efficacy could enter an optional 2-week open-label phase to receive ketamine with the same frequency as in the double-blind phase. The primary outcome measure was change from baseline to day 15 in total score on the Montgomery-&Aring;sberg Depression Rating Scale [MADRS].<\/div>\n<div align=\"justify\"><em><strong><font color=\"#200020\">Results<\/font><\/strong><\/em>: In total, 67 [45 women] of 68 randomized patients received treatment. In the twice-weekly dosing groups, the mean change in MADRS score at day 15 was -18.4 [SD=12.0] for ketamine and -5.7 [SD=10.2] for placebo; in the thrice-weekly groups, it was -17.7 [SD=7.3] for ketamine and -3.1 [SD=5.7] for placebo. Similar observations were noted for ketamine during the open-label phase [twice-weekly, -12.2 [SD=12.8] on day 4; thrice-weekly, -14.0 [SD=12.5] on day 5]. Both regimens were generally well tolerated. Headache, anxiety, dissociation, nausea, and dizziness were the most common [&gt;20%] treatment-emergent adverse events. Dissociative symptoms occurred transiently and attenuated with repeated dosing.<\/div>\n<div align=\"justify\"><em><strong><font color=\"#200020\">Conclusions<\/font><\/strong><\/em>: Twice-weekly and thrice-weekly administration of ketamine at 0.5 mg\/kg similarly maintained antidepressant efficacy over 15 days.<\/div>\n<p>                                          <\/p>\n<div align=\"center\"><img decoding=\"async\" width=\"400\" border=\"0\" src=\"http:\/\/1boringoldman.com\/images\/ketamine-2-3.gif\" \/><\/div>\n<\/blockquote>\n<div align=\"justify\" class=\"small\">In May, an article published in <strong><font color=\"#660066\">Nature<\/font><\/strong> got a lot of attention. It suggested that the psychodelic effects of Ketamine and the antidepressant effects came from different molecules. Great news, but the problem was that the finding was studied in mice, not people:                                <\/div>\n<blockquote>\n<div align=\"center\" class=\"big\"><a href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/27144355\" target=\"_blank\">NMDAR inhibition-independent antidepressant actions of ketamine metabolites<\/a>.<\/div>\n<div align=\"center\" class=\"middle\">by Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI, Alkondon M, Yuan P, Pribut HJ, Singh NS, Dossou KS, Fang Y, Huang XP, Mayo CL, Wainer IW, Albuquerque EX, Thompson SM, Thomas CJ, Zarate CA Jr, Gould TD<\/div>\n<div align=\"center\" class=\"middle\"><strong><font color=\"#660066\">Nature<\/font><\/strong>. 2016 533[7604]:481-486.<\/div>\n<p>                                 <\/p>\n<div align=\"justify\"><img decoding=\"async\" hspace=\"4\" width=\"96\" vspace=\"4\" border=\"1\" align=\"right\" src=\"http:\/\/www.ninds.nih.gov\/research\/parkinsonsweb\/amr\/Mice%20Gif.gif\" \/>Major  depressive disorder affects around 16 per cent of the world population  at some point in their lives. Despite the availability of numerous  monoaminergic-based antidepressants, most patients require several  weeks, if not months, to respond to these treatments, and many patients  never attain sustained remission of their symptoms. The non-competitive,  glutamatergic NMDAR [N-methyl-d-aspartate receptor] antagonist  [R,S]-ketamine exerts rapid and sustained antidepressant effects after a  single dose in patients with depression, but its use is associated with  undesirable side effects. Here we show that the metabolism of  [R,S]-ketamine to [2S,6S;2R,6R]-hydroxynorketamine [HNK] is essential  for its antidepressant effects, and that the [2R,6R]-HNK enantiomer  exerts behavioural, electroencephalographic, electrophysiological and  cellular antidepressant-related actions in mice. These antidepressant  actions are independent of NMDAR inhibition but involve early and  sustained activation of AMPARs [&alpha;-amino-3-hydroxy-5-methyl-4-isoxazole  propionic acid receptors]. We also establish that [2R,6R]-HNK lacks  ketamine-related side effects. Our data implicate a novel mechanism  underlying the antidepressant properties of [R,S]-ketamine and have  relevance for the development of next-generation, rapid-acting  antidepressants.<\/div>\n<\/blockquote>\n<blockquote>\n<div align=\"center\" class=\"big\"><a href=\"http:\/\/blogs.discovermagazine.com\/neuroskeptic\/2016\/05\/07\/ketamine-depression-breakthrough\/#.V7uLF15d_gx\" target=\"_blank\">Ketamine and Depression: A Breakthrough?<\/a><\/div>\n<div align=\"center\" class=\"big\"><strong><font color=\"#660066\">Discover Magazine<\/font><\/strong><\/div>\n<div align=\"center\" class=\"middle\">By Neuroskeptic<\/div>\n<div align=\"center\" class=\"middle\">May 7, 2016<\/div>\n<p align=\"justify\">In recent years there has been great research interest in ketamine as an antidepressant. Ketamine, a drug better-known for its use as an anaesthetic [and a recreational drug in lower doses] is claimed to have powerful, rapid-acting antidepressant effects, even in depressed patients who have not responded to more conventional drugs. However, its mechanism of action remains unclear.<\/p>\n<div align=\"justify\">Now, in a major new Nature paper, Baltimore researchers Panos Zanos and colleagues say that ketamine itself is probably not an antidepressant after all. Instead, the antidepressant effects can be attributed to a metabolite of the drug, formed in the body after taking ketamine. The metabolite is called [2S,6S;2R,6R]-HNK. But is this a real breakthrough or a red herring? Here&rsquo;s how Zanos et al. describe their findings:<\/div>\n<div align=\"justify\">\n<ul>\n<div>Here we show that the metabolism of [R,S]-ketamine to [2S,6S;2R,6R]-hydroxynorketamine [HNK] is essential for its antidepressant effects, and that the [2R,6R]-HNK enantiomer exerts behavioural, electroencephalo-graphic, electrophysiological and cellular antidepressant-related actions in mice.<\/div>\n<\/ul><\/div>\n<p align=\"justify\">So how does HNK do this? Unlike ketamine, HNK is not an NMDA glutamate receptor antagonist. Rather, it acts to promote signalling via the AMPA glutamate receptor. NMDA antagonism is believed to underlie ketamine&rsquo;s anaesthetic and psychoactive [dissociative hallucinogenic] properties. So HNK is not likely to have these undesirable effects, Zanos et al. say, making it more suitable as an antidepressant.<\/p>\n<div align=\"justify\">I&rsquo;ve been following the ketamine\/depression story for nearly a decade and this paper is the most interesting piece of work I&rsquo;ve seen. This is a really impressive set of experiments &ndash; but they were all in animals. Zanos et al. haven&rsquo;t shown that ketamine&rsquo;s antidepressant effects are mediated by HNK in people; rather they&rsquo;ve studied the &lsquo;antidepressant-like&lsquo; effects of ketamine in rodent behavioural models such as the forced swim test. Bottom line: we don&rsquo;t yet know whether HNK is a human antidepressant.<\/div>\n<div align=\"center\"> <img loading=\"lazy\" decoding=\"async\" height=\"18\" width=\"66\" border=\"0\" src=\"http:\/\/1boringoldman.com\/images\/snip.gif\" \/> <\/div>\n<div align=\"justify\"><img decoding=\"async\" hspace=\"4\" height=\"50\" border=\"0\" align=\"left\" src=\"http:\/\/1boringoldman.com\/images\/neuroskeptic.gif\" \/><em><strong><font color=\"#660033\">My own suspicion is that the antidepressant effects of ketamine may be driven not by a metabolite but as a kind of psychological reaction to its pronounced psychoactive effects. If HNK is non-psychoactive, I predict that it won&rsquo;t turn out to mediate ketamine&rsquo;s antidepressant effects in humans. HNK might nonetheless have some antidepressant activity but not as dramatic as ketamine. Then again I might very well be wrong, and I hope I am, because if Zanos et al. are right, they might just have discovered the next &lsquo;miracle&rsquo; antidepressant.<\/font><\/strong><\/em><\/div>\n<\/blockquote>\n<div align=\"justify\" class=\"small\">Here are a couple of other commentaries on the HNK finding:                            <\/div>\n<ul><sup>                            <\/p>\n<li><strong><font color=\"#660033\">Real Psychiatry<\/font><\/strong>: <a href=\"http:\/\/real-psychiatry.blogspot.com\/2016\/05\/latest-on-ketamine.html\" target=\"_blank\">Latest on Ketamine<\/a> <\/li>\n<li><strong><font color=\"#0066ff\">Slate Star Codex<\/font><\/strong>: <a href=\"http:\/\/slatestarcodex.com\/2016\/06\/07\/ketamine-research-in-a-new-light\/\" target=\"_blank\">Ketamine Research In A New Light<\/a><\/li>\n<p>                            <\/sup><\/ul>\n<div align=\"justify\" class=\"small\">For ever-so-long, we&#8217;ve lived in a dream world in psychopharmacology. I call it future-think, what&#8217;s coming down the <font color=\"#200020\">pipeline<\/font> or shows promise. But the pipeline is dry, and HNK, mentioned above, hasn&#8217;t even made it into humans yet. This story has one of the classic signs of future-think, a review article from Dr. Charlie Nemeroff, KOL extrordinaire. In <a href=\"http:\/\/ajp.psychiatryonline.org\/doi\/abs\/10.1176\/appi.ajp.2015.15040465?journalCode=ajp\" target=\"_blank\">Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression<\/a>, he was pushing <font color=\"#200020\">Rapastenel<\/font>, touted to be a Ketamine-ish drug with antidepressant properties but none of the club drug effects [see <a href=\"http:\/\/1boringoldman.com\/index.php\/2015\/10\/07\/a-touch-of-paralysis\/\" target=\"_blank\">a touch of paralysis&hellip;<\/a>]. Nemeroff earlier went out of his way to assure us he had no COI with the drug. However, right after the review article came out, the drug and its company was bought up by <font color=\"#200020\">Allergan<\/font>, one of Dr. Nemeroff&#8217;s COI companies [<a target=\"_blank\" href=\"http:\/\/www.fiercebiotech.com\/story\/after-560m-allergan-buyout-naurex-vets-regroup-cns-rd\/2015-09-16\">After a $560M Allergan buyout, Naurex vets regroup for CNS R&amp;D<\/a>] [up to his old tricks?]. It&#8217;s based on a single <em><font color=\"#200020\">proof of concept<\/font><\/em> study [<a target=\"_blank\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/25782764\">Randomized proof of concept trial of GLYX-13, an  N-methyl-D-aspartate receptor glycine site partial agonist, in major  depressive disorder nonresponsive to a previous antidepressant agent<\/a>], marginal if even that, but somehow Allergan got it on the fast track [<a href=\"http:\/\/www.prnewswire.com\/news-releases\/allergans-rapastinel-receives-fda-breakthrough-therapy-designation-for-adjunctive-treatment-of-major-depressive-disorder-mdd-300212027.html\" target=\"_blank\">Allergan&#8217;s Rapastinel Receives FDA Breakthrough Therapy Designation for Adjunctive Treatment of Major Depressive Disorder [MDD]<\/a>]. They advertize Phase III trials in the offing, but none are registered on clinicaltrials.gov that I can locate. <font color=\"#200020\">So I wouldn&#8217;t say Rapastenel is either in the pipeline or yet even a drug of promise, but it&#8217;s being discussed as if it is the next great something-or-another.<\/font><\/div>\n<p align=\"justify\" class=\"small\">And <font color=\"#200020\">Janssen<\/font> is certainly going forward full bore with <font color=\"#200020\">Esketamine intravenous and intranasal<\/font> [see <a href=\"http:\/\/1boringoldman.com\/index.php\/2016\/08\/18\/the-best-predictor-5\/\" target=\"_blank\">the best predictor&hellip;<\/a> and <a href=\"http:\/\/www.jnj.com\/news\/all\/Esketamine-Receives-Breakthrough-Therapy-Designation-from-US-Food-and-Drug-Administration-for-Major-Depressive-Disorder-with-Imminent-Risk-for-Suicide\" target=\"_blank\">Esketamine    Receives Breakthrough Therapy Designation from U.S.  Food and Drug    Administration for Major Depressive Disorder with  Imminent Risk for    Suicide<\/a>]. When I looked at their recent study earlier [<a target=\"_blank\" href=\"http:\/\/www.biologicalpsychiatryjournal.com\/article\/S0006-3223%2815%2900914-2\/fulltext\">Intravenous Esketamine in Adult Treatment-Resistant Depression: A Double-Blind, Double-Randomization, Placebo-Controlled Study<\/a>], I focused on efficacy and didn&#8217;t pay enough attention to the club drug effect. They assessed it with both the <font color=\"#200020\">Brief Psychiatric Rating Scale <\/font>[<font color=\"#200020\">BPRS<\/font>] total score and the <font color=\"#200020\">Clinician Administered Dissociative States Scale <\/font>[<font color=\"#200020\">CADSS<\/font>] total score [which roughly paralleled each other]. The upper figure is the BPRS data from the paper and the lower versions are redrawn with an accurate x-axis timeline [because I am suspicious of irregular scales in graphic presentations]. It looks like about a 2 &#8211; 4 hour &quot;<font color=\"#200020\">high<\/font>&quot;:<\/p>\n<p align=\"center\" class=\"small\"><img decoding=\"async\" width=\"400\" border=\"0\" src=\"http:\/\/1boringoldman.com\/images\/esketamine-x.gif\" \/><\/p>\n<blockquote>\n<div align=\"justify\">&quot;Similar to ketamine, esketamine led to transient dissociative and psychotic symptoms. According to CADSS severity categories,  the peak mean CADSS total scores at 40 minutes postinfusion on day 1  for the esketamine .20 mg\/kg and .40 mg\/kg groups would be categorized  as high. However, symptoms subsided to baseline levels within 4 hours.  The CADSS scores showed evidence of dose dependence on each DB dosing  day. A similar pattern was observed for psychotic-like effects measured  using BPRS total scores. These results are similar to results of IV  ketamine studies.&quot;<\/div>\n<\/blockquote>\n<p align=\"justify\" class=\"small\">The intranasal form [study not yet&nbsp; published that I can find &#8211; <font color=\"#200020\">reference: Canuso C, et al. &quot;Esketamine for  the  Rapid Reduction of the Symptoms of  Major Depressive Disorder,   Including Suicidal Ideation, in Subjects  Assessed to be at Imminent   Risk for Suicide.&quot; Society of Biological  Psychiatry 71<sup>st<\/sup> Annual Scientific Meeting. <span class=\"xn-chron\">May 12-14, 2016]<\/span><\/font> may be an improvement in terms of a delivery system, but it&#8217;s not apparent to me how <font color=\"#200020\">Esketamine<\/font> makes any advances over the already available racemic mixture of <font color=\"#200020\">Ketamine<\/font> in terms of either efficacy or absence of club drug effects.<\/p>\n<hr size=\"1\" \/>                     <\/p>\n<div align=\"justify\" class=\"small\">I am perhaps even more skeptical than Neuroskeptic that the transient antidepressant effect that follows the psychodelic effect of these drugs can be isolated as the &quot;<em><font color=\"#660033\">the next &lsquo;miracle&rsquo; antidepressant<\/font><\/em>&quot; &#8211; agreeing with him that the effect is likely a linked consequence of the drug&#8217;s mind-altering experience. But beyond that, I think of <font color=\"#200020\">Ketamine<\/font> as a <em><font color=\"#200020\">feel good<\/font><\/em> drug rather than an antidepressant, adding a <em><font color=\"#200020\">good feeling<\/font><\/em> instead of ameliorating the target emotion &#8211; depression. I question whether this is a rational direction for psychiatric treatment to pursue.<\/div>\n<div align=\"center\" class=\"small\"><a href=\"http:\/\/1boringoldman.com\/images\/pipeline-2.gif\" target=\"_blank\"><img decoding=\"async\" width=\"500\" border=\"0\" src=\"http:\/\/1boringoldman.com\/images\/pipeline-1.gif\" \/><\/a><br \/>         <sup>[click image for the SSRis, SNRIs, and Atypicals by the  year of Approval]<\/sup><\/div>\n<p>        <\/p>\n<div align=\"justify\" class=\"small\">While the debates about the psychoactive drugs that have flowed from the pharmaceutical pipeline [see <a href=\"http:\/\/1boringoldman.com\/index.php\/2016\/03\/31\/the-pipeline-paradigm\/\">the pipeline paradigm&hellip;<\/a>] have covered lots of territory over the last thirty-five years, at least we haven&#8217;t had to deal so much with the problems of an earlier generation &#8211; drug abuse [Benzodiazepines, Barbituates, Meprobamate, etc.]. Ketamine adds that back into the equation. It is already a widely abused street drug, and there&#8217;s no reason to doubt that its use as an antidepressant will dramatically expand its abuse potential &#8211; particularly if there&#8217;s <strike><em><font color=\"#200020\">an intranasal<\/font><\/em><\/strike> <em><font color=\"#200020\">a snortable<\/font><\/em> version. It may be consistent with the goals of the pharmaceutical industry [sell more drugs] or managed care [cut hospitalization costs], but this feels like <em><font color=\"#200020\">no country<\/font><\/em> for psychiatry [or our patients] &#8211; like a time to be careful rather than in a rush. So I question the FDA fast-tracking either <font color=\"#200020\">Rapastinel<\/font> or <font color=\"#200020\">Esketamine<\/font> by granting <font color=\"#200020\">Breakthrough Therapy Designation<\/font>. If a non-psychodelic antidepressant actually comes from this line of thinking down the road, then that might be reasonable. But for the moment, Ketamine&#8217;s cousins remain inhabitants of the realm of speculation and entrepreneurialism, hardly candidates for the fast lane&#8230;<\/div>\n","protected":false},"excerpt":{"rendered":"<p>Nosing around about Ketamine, I ran across this draft that I never posted from 2&frac12; years ago: from February 19, 2014: Neuroskeptic has an interesting thing going trying to figure out if the effect on depressed people from Ketamine is because Ketamine is a pharmacologic antidepressant, or, to put it in my own worlds, does [&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":[5],"tags":[],"class_list":["post-67651","post","type-post","status-publish","format-standard","hentry","category-opinion"],"_links":{"self":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/67651","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=67651"}],"version-history":[{"count":108,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/67651\/revisions"}],"predecessor-version":[{"id":67859,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/67651\/revisions\/67859"}],"wp:attachment":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/media?parent=67651"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/categories?post=67651"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/tags?post=67651"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}