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      Double-Blind, Placebo-Controlled, Dose-Ranging Trial of Intravenous Ketamine as Adjunctive Therapy in Treatment-Resistant Depression (TRD)

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          Abstract

          Numerous placebo-controlled studies have demonstrated the ability of ketamine, an NMDA receptor antagonist, to induce rapid (within hours), transient antidepressant effects when administered intravenously (IV) at subanesthetic doses (0.5mg/kg over 40 minutes). However, the optimal antidepressant dose remains unknown. We aimed to compare to active placebo the rapid acting antidepressant properties of a broad range of subanesthetic doses of IV ketamine among outpatients with treatment-resistant depression (TRD). A range of IV ketamine doses were compared to active placebo in the treatment of adult TRD over a 3-day period following a single infusion over 40 minutes. This was an outpatient study conducted across six US academic sites. Outpatients 18–70 years old with TRD, defined as failure to achieve a satisfactory response (e.g., less than 50% improvement of depression symptoms) to at least two adequate treatment courses during the current depressive episode. Following a washout period, 99 eligible subjects were randomly assigned to one of five arms in a 1:1:1:1:1 fashion: a single intravenous dose of ketamine 0.1 mg/kg (n=18), a single dose of ketamine 0.2 mg/kg (n=20), a single dose of ketamine 0.5 mg/kg (n=22), a single dose of ketamine 1.0 mg/kg (n=20), and a single dose of midazolam 0.045 mg/kg (active placebo) (n=19). The study assessments (HAM-D-6, MADRS. SDQ, PAS, CGI-S and CGI-I) were performed at Days 0, 1, 3 (endpoint), 5, 7, 14, and 30 to assess the safety and efficacy. The overall group*time interaction effect was significant for the primary outcome measure, the HAM-D-6. In post-hoc pairwise comparisons controlling for multiple comparisons standard- (0.5 mg/kg) and high-doses (1 mg/kg) of intravenous ketamine were superior to active placebo; a low-dose (0.1 mg/kg) was significant only prior to adjustment (p=0.02, p-adj=0.14, d=−0.82 at Day 1). Most of the interaction effect was due to differences at Day 1, with no significant adjusted pairwise differences at Day 3. This pattern generally held for secondary outcomes. The infusions of ketamine were relatively well tolerated compared to active placebo, except for greater dissociative symptoms and transient blood pressure elevations with the higher doses. Our results suggest that there is evidence for the efficacy of the 0.5 mg/Kg and 1.0 mg/Kg subanesthetic doses of IV ketamine and no clear or consistent evidence for clinically meaningful efficacy of lower doses of IV ketamine. Trial Registration: NCT01920555.

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          Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: a multisite randomized controlled trial.

          We tested whether transcranial magnetic stimulation (TMS) over the left dorsolateral prefrontal cortex (DLPFC) is effective and safe in the acute treatment of major depression. In a double-blind, multisite study, 301 medication-free patients with major depression who had not benefited from prior treatment were randomized to active (n = 155) or sham TMS (n = 146) conditions. Sessions were conducted five times per week with TMS at 10 pulses/sec, 120% of motor threshold, 3000 pulses/session, for 4-6 weeks. Primary outcome was the symptom score change as assessed at week 4 with the Montgomery-Asberg Depression Rating Scale (MADRS). Secondary outcomes included changes on the 17- and 24-item Hamilton Depression Rating Scale (HAMD) and response and remission rates with the MADRS and HAMD. Active TMS was significantly superior to sham TMS on the MADRS at week 4 (with a post hoc correction for inequality in symptom severity between groups at baseline), as well as on the HAMD17 and HAMD24 scales at weeks 4 and 6. Response rates were significantly higher with active TMS on all three scales at weeks 4 and 6. Remission rates were approximately twofold higher with active TMS at week 6 and significant on the MADRS and HAMD24 scales (but not the HAMD17 scale). Active TMS was well tolerated with a low dropout rate for adverse events (4.5%) that were generally mild and limited to transient scalp discomfort or pain. Transcranial magnetic stimulation was effective in treating major depression with minimal side effects reported. It offers clinicians a novel alternative for the treatment of this disorder.
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            Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial.

            Ketamine, a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist, has shown rapid antidepressant effects, but small study groups and inadequate control conditions in prior studies have precluded a definitive conclusion. The authors evaluated the rapid antidepressant efficacy of ketamine in a large group of patients with treatment-resistant major depression. This was a two-site, parallel-arm, randomized controlled trial of a single infusion of ketamine compared to an active placebo control condition, the anesthetic midazolam. Patients with treatment-resistant major depression experiencing a major depressive episode were randomly assigned under double-blind conditions to receive a single intravenous infusion of ketamine or midazolam in a 2:1 ratio (N=73). The primary outcome was change in depression severity 24 hours after drug administration, as assessed by the Montgomery-Åsberg Depression Rating Scale (MADRS). The ketamine group had greater improvement in the MADRS score than the midazolam group 24 hours after treatment. After adjustment for baseline scores and site, the MADRS score was lower in the ketamine group than in the midazolam group by 7.95 points (95% confidence interval [CI], 3.20 to 12.71). The likelihood of response at 24 hours was greater with ketamine than with midazolam (odds ratio, 2.18; 95% CI, 1.21 to 4.14), with response rates of 64% and 28%, respectively. Ketamine demonstrated rapid antidepressant effects in an optimized study design, further supporting NMDA receptor modulation as a novel mechanism for accelerated improvement in severe and chronic forms of depression. More information on response durability and safety is required before implementation in clinical practice.
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              • Article: not found

              Antidepressant effects of ketamine in depressed patients.

              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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                Author and article information

                Contributors
                Role: Director
                Journal
                9607835
                20545
                Mol Psychiatry
                Mol. Psychiatry
                Molecular psychiatry
                1359-4184
                1476-5578
                7 September 2018
                03 October 2018
                04 April 2019
                : 10.1038/s41380-018-0256-5
                Affiliations
                [1 ]Massachusetts General Hospital
                [2 ]Baylor College of Medicine/Michael E. Debakey VA Medical Center
                [3 ]Icahn School of Medicine at Mount Sinai
                [4 ]Stanford University School of Medicine
                [5 ]University of Texas Southwestern
                [6 ]Yale University
                Author notes

                Marlene Freeman:

                Over the past three years, Dr. Freeman has received research support from: Takeda, JayMac, and Sage; she has served in advisory boards of: Janssen, Sage, JDS therapeutics, Sunovion, and Takeda; she has served in the Independent Data Safety and Monitoring Committee of Janssen (Johnson& Johnson); she has served as a medical editor for the GOED newsletter.

                Sanjay J. Mathew:

                Over the past 3 years, Dr. Mathew has received consulting fees from Acadia, Alkermes, Allergan, Bracket, Cerecor, Fortress Biotech, Otsuka, and Valeant; He has received research support from: Janssen and NeuroRx. He has also received support from facilities and resources of the Michael E. Debakey VA Medical Center and the Johnson Chair for Research from Baylor College of Medicine.

                James Murrough:

                In the past 3 years, Dr. Murrough has provided consultation services to Allergan, Fortress Biotech, Novartis, Janssen Research and Development, Genentech, and ProPhase and has received research support from Avanir Pharmaceuticals. Dr. Murrough is named on a patent pending for neuropeptide Y as a treatment for mood and anxiety disorders as well as on patents pending for lithium to extend the antidepressant effect of ketamine and ketamine plus lithium as a treatment for suicidal ideation. The Icahn School of Medicine (employer of Dr. Murrough) is named on a patent and has entered into a licensing agreement and will receive payments related to the use of ketamine if it is approved for the treatment of depression. Dr. Murrough is not named on this patent and will not receive any payments.

                Alan Schatzberg:

                Dr. Schatzberg has served as a consultant for Alkermes, Avanir, Bracket, Lundbeck/Takeda, McKinsey, Myriad Genetics, Neuronetics and Owl and as a speaker for Merck and Pfizer; he holds equity in Corcept (co-founder), Gilead, Incyte, Intersect ENT, Merck, Owl, Seattle Genetics, Titan, and Xhale; he has research funding from Janssen; and he is listed as an inventor on pharmacogenetic and mifepristone patents from Stanford University.

                George I. Papakostas:

                Over the past three years, Dr. Papakostas has consulted to: Lundbeck, Sunovion, Brainsway, Pfizer, Boston Pharmaceuticals*, Novartis*, Acadia*, Axsome*, Genomind*, and Mylan*(*on behalf of Massachusetts General Hospital). He has received honoraria from: Lundbeck, Grunbiotics-Mylan, Takeda, Alkermes, Pfizer, Pharma Trade SAS, Asofarma, Sunovion, Brainsway, and Unilab Philippines. He has received research support from Neuralstem Inc and Tal Medical.

                Gerard Sanacora:

                Dr. Sanacora has received consulting fees form Allergan, Alkermes, AstraZeneca, Biohaven Pharmaceuticals, Genentech, Janssen, Lundbeck, Merck, Navitor pharmaceuticals, Noven pharmaceuticals, Sage Pharmaceuticals, Takeda, Taisho Pharmaceuticals, Teva Pharmaceuticals and Vistagen Therapeutics over the last 36 months. He has also received additional research contracts from AstraZeneca, Bristol-Myers Squibb, Eli Lilly & Co., Johnson & Johnson, Hoffman La-Roche, Merck & Co., Naurex and Servier over the last 36 months. Free medication was provided to Dr. Sanacora for an NIH sponsored study by Sanofi-Aventis. In addition, he holds shares in Biohaven Pharmaceuticals and is a co-inventor on a patent “Glutamate agents in the treatment of mental disorders” Patent number: 8778979

                Madhukar Trivedi:

                Consulting/Advisory Board: Alkeremes Inc., Akili Interactive, Allergan Pharmaceuticals, Arcadia Pharmaceuticals, Avanir Pharmaceuticals, Brintellix Global, Bristol Myers Squibb, Caudex, Cerecor, Forest Pharmaceuticals, Global Medical Education Inc, Health Research Associates, Insys, Johnson & Johnson Pharmaceutical Research & Development, Lilly Research Laboratories, Lundbeck Research USA, Medscape, Merck & Co. Inc, Mitsubishi Pharma, MSI Methylation Sciences – Pamlab Inc., Navitor, Otsuka America Pharmaceutical Inc., One Carbon Therapeutics, Otsuka America Pharmaceutical Inc., Pfizer Inc, Takeda Global Research

                Royalties: Janssen Research and Development LLC

                Author Agreement: Janssen Asia Pacific, Oxford University Press

                Honoraria: American Psychiatric Association

                Address correspondence to: Maurizio Fava M.D, Director, Division of Clinical Research of the MGH Research Institute, Executive Vice Chair, Department of Psychiatry, Executive Director, Clinical Trials Network and Institute (CTNI), Massachusetts General Hospital (MGH), Associate Dean for Clinical and Translational Research, Slater Family Professor of Psychiatry, Harvard Medical School, Mailing Address, Massachusetts General Hospital, 55 Fruit Street, Bulfinch 351, Boston MA 02114, Tel: 617-724-0838 Fax: 617-726-2688, mfava@ 123456mgh.harvard.edu
                Article
                NIHMS1506073
                10.1038/s41380-018-0256-5
                6447473
                30283029
                7f143955-ad0e-4625-bfb5-4d5a6de218ce

                Royalty/patent, other income: Patents for Sequential Parallel Comparison Design (SPCD), licensed by MGH to Pharmaceutical Product Development, LLC (PPD) (US_7840419, US_7647235, US_7983936, US_8145504, US_8145505); and patent application for a combination of Ketamine plus Scopolamine in Major Depressive Disorder (MDD), licensed by MGH to Biohaven. Patents for pharmacogenomics of Depression Treatment with Folate (US_9546401, US_9540691).

                Copyright for the MGH Cognitive & Physical Functioning Questionnaire (CPFQ), Sexual Functioning Inventory (SFI), Antidepressant Treatment Response Questionnaire (ATRQ), Discontinuation-Emergent Signs & Symptoms (DESS), Symptoms of Depression Questionnaire (SDQ), and SAFER; Lippincott, Williams & Wilkins; Wolkers Kluwer; World Scientific Publishing Co. Pte.Ltd.

                Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

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