Family history of alcohol dependence and initial antidepressant response to an N-methyl-D-aspartate antagonist.

Laboratory of Molecular Pathophysiology and Experimental Therapeutics, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health/DHHS, 10 Center Drive, Bethesda, MD 20892-1282, USA.
Biological psychiatry (Impact Factor: 8.93). 12/2008; 65(2):181-4. DOI: 10.1016/j.biopsych.2008.09.029
Source: PubMed

ABSTRACT A high rate of comorbidity exists between mood disorders and alcohol dependence. Furthermore, both ketamine, a dissociative anesthetic with a recently described rapid-onset antidepressant effect, and ethanol are N-methyl-D-aspartate (NMDA) receptor antagonists. Previous investigations of healthy individuals with a family history of alcohol dependence have found that these individuals have an attenuated response to ketamine's perceptual disturbance and dysphoric effects similar to that found in individuals with a self-reported history of alcohol dependence. This study investigated whether a family history of alcohol dependence influences ketamine's initial antidepressant effect.
Twenty-six subjects with DSM-IV treatment-resistant major depression were given an open-label intravenous infusion of ketamine hydrochloride (.5 mg/kg) and rated using various depression scales at baseline, 40, 80, 120, and 230 min postinfusion. The primary outcome measure was Montgomery-Asberg Depression Rating Scale (MADRS) scores.
Subjects with a family history of alcohol dependence showed significantly greater improvement in MADRS scores compared with subjects who had no family history of alcohol dependence.
A family history of alcohol dependence appears to predict a rapid initial antidepressant response to an NMDA receptor antagonist.

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    ABSTRACT: 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. 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). 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). Ketamine's extended antidepressant durability in FHP TRD should be considered in the design and analysis of ketamine depression trials. 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.
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    ABSTRACT: N-methyl-D-aspartate receptor antagonists, such as ketamine, have rapid antidepressant effects in patients with treatment-resistant depression (TRD). We hypothesized that nitrous oxide, an inhalational general anesthetic and N-methyl-D-aspartate receptor antagonist, may also be a rapidly acting treatment for TRD. In this blinded, placebo-controlled crossover trial, 20 patients with TRD were randomly assigned to 1-hour inhalation of 50% nitrous oxide/50% oxygen or 50% nitrogen/50% oxygen (placebo control). The primary endpoint was the change on the 21-item Hamilton Depression Rating Scale (HDRS-21) 24 hours after treatment. Mean duration of nitrous oxide treatment was 55.6 ± 2.5 (SD) min at a median inspiratory concentration of 44% (interquartile range, 37%-45%). In two patients, nitrous oxide treatment was briefly interrupted, and the treatment was discontinued in three patients. Depressive symptoms improved significantly at 2 hours and 24 hours after receiving nitrous oxide compared with placebo (mean HDRS-21 difference at 2 hours, -4.8 points, 95% confidence interval [CI], -1.8 to -7.8 points, p = .002; at 24 hours, -5.5 points, 95% CI, -2.5 to -8.5 points, p < .001; comparison between nitrous oxide and placebo, p < .001). Four patients (20%) had treatment response (reduction ≥50% on HDRS-21) and three patients (15%) had a full remission (HDRS-21 ≤ 7 points) after nitrous oxide compared with one patient (5%) and none after placebo (odds ratio for response, 4.0, 95% CI, .45-35.79; OR for remission, 3.0, 95% CI, .31-28.8). No serious adverse events occurred; all adverse events were brief and of mild to moderate severity. This proof-of-concept trial demonstrated that nitrous oxide has rapid and marked antidepressant effects in patients with TRD. Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
    Biological Psychiatry 12/2014; DOI:10.1016/j.biopsych.2014.11.016 · 9.47 Impact Factor
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    ABSTRACT: This literature review begins with a rationale for the development of new therapeutic approaches for the treatment of depressive disorder. In the following sections the history of the finding of ketamine‘s antidepressant effect, its pharmacological properties and application routes are summarized. The following is an overview of the existing scientific evidence of ketamine’s efficacy in patients with unipolar and bipolar depression, suicidality and the adjuvant use in electroconvulsive therapy. Finally, the author discusses acute and chronic side effects, safety of repeated administration of ketamine and possibilities of extending the antidepressant effect. The last section summarizes recent findings on the mechanism of the antidepressant effect of ketamine on the molecular level and its effect on neuronal plasticity.
    Psychiatrie 01/2014; 18(4):193-205.

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