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      Ketamine’s Antidepressant Efficacy is Extended for at Least Four Weeks in Subjects with a Family History of an Alcohol Use Disorder

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          Abstract

          Background:

          A single subanesthetic infusion of the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has rapid and potent antidepressant properties in treatment-resistant major depressive disorder (TRD). As a family history of an alcohol use disorder is a positive predictor of ketamine’s antidepressant response and the strength of the association increases over time, we hypothesized that depressed subjects with a family history of an alcohol use disorder would have greater antidepressant durability and that riluzole would augment and/or extend ketamine’s antidepressant efficacy.

          Methods:

          Fifty-two TRD subjects received an open-label infusion of ketamine (0.5mg/kg over 40 minutes), and, four to six hours post-infusion, were randomized to either flexible-dose (100–200mg/day) riluzole or placebo in the following proportions: Family History Positive (FHP) riluzole (n = 10), FHP placebo (n = 9), Family History Negative (FHN) riluzole (n = 16), and FHN placebo (n = 17).

          Results:

          FHP subjects randomized to placebo had a greater antidepressant response than FHN subjects; however, contrary to our initial hypothesis, there was no significant difference in antidepressant efficacy with riluzole. Although potentially underpowered, there was no difference in overall time-to-relapse based on randomization status (riluzole responders: n = 15, placebo responders: n = 17). Yet, time-to-relapse was longer in FHP placebo responders (n = 8) compared to FHN placebo responders (n = 9) with, again, no significant difference in time-to-relapse in FHP riluzole responders (n = 6) compared to FHN riluzole responders (n = 9).

          Conclusions:

          Ketamine’s extended antidepressant durability in FHP TRD should be considered in the design and analysis of ketamine depression trials.

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          Most cited references 30

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          A rating scale for mania: reliability, validity and sensitivity.

          An eleven item clinician-administered Mania Rating Scale (MRS) is introduced, and its reliability, validity and sensitivity are examined. There was a high correlation between the scores of two independent clinicians on both the total score (0.93) and the individual item scores (0.66 to 0.92). The MRS score correlated highly with an independent global rating, and with scores of two other mania rating scales administered concurrently. The score also correlated with the number of days of subsequent stay in hospital. It was able to differentiate statistically patients before and after two weeks of treatment and to distinguish levels of severity based on the global rating.
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            Global burden of depressive disorders in the year 2000.

            The initial Global Burden of Disease study found that depression was the fourth leading cause of disease burden, accounting for 3.7% of total disability adjusted life years (DALYs) in the world in 1990. To present the new estimates of depression burden for the year 2000. DALYs for depressive disorders in each world region were calculated, based on new estimates of mortality, prevalence, incidence, average age at onset, duration and disability severity. Depression is the fourth leading cause of disease burden, accounting for 4.4% of total DALYs in the year 2000, and it causes the largest amount of non-fatal burden, accounting for almost 12% of all total years lived with disability worldwide. These data on the burden of depression worldwide represent a major public health problem that affects patients and society.
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              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

                Journal
                Int J Neuropsychopharmacol
                Int. J. Neuropsychopharmacol
                ijnp
                ijnp
                International Journal of Neuropsychopharmacology
                Oxford University Press (US )
                1461-1457
                1469-5111
                January 2015
                19 December 2014
                : 18
                : 1
                Affiliations
                National Institutes of Health/National Institute of Mental Health, Experimental Therapeutics and Pathophysiology Branch , Bethesda, MD (Drs Niciu, Ionescu, Richards, Vande Voort, Ballard, Furey, and Zarate, Mr Luckenbaugh, and Ms Brutsche).
                Author notes
                Correspondence: Mark J. Niciu, MD, PhD, National Institutes of Health/National Institute of Mental Health, Experimental Therapeutics and Pathophysiology Branch, 10 Center Drive, Building 10/CRC, Room 7-5545, Bethesda, MD 20892 ( mark.niciu@ 123456nih.gov ).
                Article
                10.1093/ijnp/pyu039
                4303351
                25539512
                Published by Oxford University Press on behalf of CINP 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.
                Page count
                Pages: 7
                Categories
                Research Article

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