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      Reduction of dopamine D 2/3 receptor binding in the striatum after a single administration of esketamine, but not R-ketamine: a PET study in conscious monkeys

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          Abstract

          R-ketamine appears to be a potent, long-lasting and safer antidepressant, relative to esketamine (S-ketamine), since it might be free of psychotomimetic side effects. Using [ 11C]raclopride and positron emission tomography (PET), we investigated whether esketamine and R-ketamine can affect dopamine D 2/3 receptor binding in the conscious monkey brain. A single infusion of esketamine (0.5 mg/kg), but not R-ketamine (0.5 mg/kg), caused a reduction of binding availability of dopamine D 2/3 receptor in the monkey striatum. This study suggests that unlike to R-ketamine, esketamine can cause dopamine release in the striatum, and that its release might be associated with psychotomimetic effects of esketamine.

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          Antidepressant effects of ketamine in depressed patients.

          R Berman, A Cappiello, A. Anand … (2000)
          A growing body of preclinical research suggests that brain glutamate systems may be involved in the pathophysiology of major depression and the mechanism of action of antidepressants. This is the first placebo-controlled, double-blinded trial to assess the treatment effects of a single dose of an N-methyl-D-aspartate (NMDA) receptor antagonist in patients with depression. Seven subjects with major depression completed 2 test days that involved intravenous treatment with ketamine hydrochloride (.5 mg/kg) or saline solutions under randomized, double-blind conditions. Subjects with depression evidenced significant improvement in depressive symptoms within 72 hours after ketamine but not placebo infusion (i.e., mean 25-item Hamilton Depression Rating Scale scores decreased by 14 +/- SD 10 points vs. 0 +/- 12 points, respectively during active and sham treatment). These results suggest a potential role for NMDA receptor-modulating drugs in the treatment of depression.
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            A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression.

            Nancy Diazgranados, Lobna Ibrahim, Nancy Brutsche … (2010)
            Existing therapies for bipolar depression have a considerable lag of onset of action. Pharmacological strategies that produce rapid antidepressant effects-for instance, within a few hours or days-would have an enormous impact on patient care and public health. To determine whether an N-methyl-D-aspartate-receptor antagonist produces rapid antidepressant effects in subjects with bipolar depression. A randomized, placebo-controlled, double-blind, crossover, add-on study conducted from October 2006 to June 2009. Mood Disorders Research Unit at the National Institute of Mental Health, Bethesda, Maryland. Patients Eighteen subjects with DSM-IV bipolar depression (treatment-resistant). Subjects maintained at therapeutic levels of lithium or valproate received an intravenous infusion of either ketamine hydrochloride (0.5 mg/kg) or placebo on 2 test days 2 weeks apart. The Montgomery-Asberg Depression Rating Scale was used to rate subjects at baseline and at 40, 80, 110, and 230 minutes and on days 1, 2, 3, 7, 10, and 14 postinfusion. Change in Montgomery-Asberg Depression Rating Scale primary efficacy measure scores. Within 40 minutes, depressive symptoms significantly improved in subjects receiving ketamine compared with placebo (d = 0.52, 95% confidence interval [CI], 0.28-0.76); this improvement remained significant through day 3. The drug difference effect size was largest at day 2 (d = 0.80, 95% CI, 0.55-1.04). Seventy-one percent of subjects responded to ketamine and 6% responded to placebo at some point during the trial. One subject receiving ketamine and 1 receiving placebo developed manic symptoms. Ketamine was generally well tolerated; the most common adverse effect was dissociative symptoms, only at the 40-minute point. In patients with treatment-resistant bipolar depression, robust and rapid antidepressant effects resulted from a single intravenous dose of an N-methyl-D-aspartate antagonist.
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              Replication of ketamine's antidepressant efficacy in bipolar depression: a randomized controlled add-on trial.

              Carlos A Zarate, Nancy Brutsche, Lobna Ibrahim … (2012)
              Currently, no pharmacological treatments for bipolar depression exist that exert rapid (within hours) antidepressant or antisuicidal effects. We previously reported that intravenous administration of the N-methyl-D-aspartate antagonist ketamine produced rapid antidepressant effects in patients with treatment-resistant bipolar depression. The present study sought to replicate this finding in an independent sample. In this double-blind, randomized, crossover, placebo-controlled study, 15 subjects with DSM-IV bipolar I or II depression maintained on therapeutic levels of lithium or valproate received a single intravenous infusion of either ketamine hydrochloride (.5 mg/kg) or placebo on 2 test days 2 weeks apart. The primary outcome measure was the Montgomery-Asberg Depression Rating Scale, which was used to rate overall depressive symptoms at baseline; at 40, 80, 110, and 230 minutes postinfusion; and on days 1, 2, 3, 7, 10, and 14 postinfusion. Within 40 minutes, depressive symptoms, as well as suicidal ideation, significantly improved in subjects receiving ketamine compared with placebo (d = .89, 95% confidence interval = .61-1.16, and .98, 95% confidence interval = .64-1.33, respectively); this improvement remained significant through day 3. Seventy-nine percent of subjects responded to ketamine and 0% responded to placebo at some point during the trial. The most common side effect was dissociative symptoms, which occurred only at the 40-minute time point. This study replicated our previous finding that patients with bipolar depression who received a single ketamine infusion experienced a rapid and robust antidepressant response. In addition, we found that ketamine rapidly improved suicidal ideation in these patients. Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Kenji Hashimoto: +81-43-226-2517 , hashimoto@faculty.chiba-u.jp
                Journal
                Journal ID (nlm-ta): Eur Arch Psychiatry Clin Neurosci
                Journal ID (iso-abbrev): Eur Arch Psychiatry Clin Neurosci
                Title: European Archives of Psychiatry and Clinical Neuroscience
                Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )
                ISSN (Print): 0940-1334
                ISSN (Electronic): 1433-8491
                Publication date (Electronic): 18 April 2016
                Publication date PMC-release: 18 April 2016
                Publication date (Print): 2017
                Volume: 267
                Issue: 2
                Pages: 173-176
                Affiliations
                [1 ]GRID grid.411500.1, Division of Clinical Neuroscience, , Chiba University Center for Forensic Mental Health, Chiba, ; 1-8-1 Inohana, Chiba, Chiba 260-8670 Japan
                [2 ]ISNI 0000 0000 9931 8289, GRID grid.450255.3, Central Research Laboratory, , Hamamatsu Photonics KK, ; Hamamatsu, Shizuoka 434-0041 Japan
                Article
                Publisher ID: 692
                DOI: 10.1007/s00406-016-0692-7
                PMC ID: 5323469
                PubMed ID: 27091456
                SO-VID: de9c0c0f-b37a-4f1c-9e4f-7b286e319f45
                Copyright © © The Author(s) 2016
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                Date received : 19 February 2016
                Date accepted : 11 April 2016
                Categories
                Subject: Short Communication
                Custom metadata
                issue-copyright-statement © Springer-Verlag Berlin Heidelberg 2017

                ScienceOpen disciplines: Neurosciences
                Keywords: dopamine d2/3 receptor,esketamine,release,r-ketamine,monkey
                Data availability:
                ScienceOpen disciplines: Neurosciences
                Keywords: dopamine d2/3 receptor, esketamine, release, r-ketamine, monkey

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