A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression

National Institute of Mental Health (NIMH), 베서스다, Maryland, United States
Archives of General Psychiatry (Impact Factor: 14.48). 09/2006; 63(8):856-64. DOI: 10.1001/archpsyc.63.8.856
Source: PubMed

ABSTRACT Existing therapies for major depression have a lag of onset of action of several weeks, resulting in considerable morbidity. Exploring pharmacological strategies that have rapid onset of antidepressant effects within a few days and that are sustained would have an enormous impact on patient care. Converging lines of evidence suggest the role of the glutamatergic system in the pathophysiology and treatment of mood disorders.
To determine whether a rapid antidepressant effect can be achieved with an antagonist at the N-methyl-D-aspartate receptor in subjects with major depression.
A randomized, placebo-controlled, double-blind crossover study from November 2004 to September 2005.
Mood Disorders Research Unit at the National Institute of Mental Health. Patients Eighteen subjects with DSM-IV major depression (treatment resistant).
After a 2-week drug-free period, subjects were given an intravenous infusion of either ketamine hydrochloride (0.5 mg/kg) or placebo on 2 test days, a week apart. Subjects were rated at baseline and at 40, 80, 110, and 230 minutes and 1, 2, 3, and 7 days postinfusion. Main Outcome Measure Changes in scores on the primary efficacy measure, the 21-item Hamilton Depression Rating Scale.
Subjects receiving ketamine showed significant improvement in depression compared with subjects receiving placebo within 110 minutes after injection, which remained significant throughout the following week. The effect size for the drug difference was very large (d = 1.46 [95% confidence interval, 0.91-2.01]) after 24 hours and moderate to large (d = 0.68 [95% confidence interval, 0.13-1.23]) after 1 week. Of the 17 subjects treated with ketamine, 71% met response and 29% met remission criteria the day following ketamine infusion. Thirty-five percent of subjects maintained response for at least 1 week.
Robust and rapid antidepressant effects resulted from a single intravenous dose of an N-methyl-D-aspartate antagonist; onset occurred within 2 hours postinfusion and continued to remain significant for 1 week.

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Available from: Jaskaran Singh, Sep 25, 2015
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    • "The now widely replicated observation that a single subanaesthetic dose of ketamine can have rapid antidepressant effects (Berman et al., 2000; Zarate et al., 2006b; Murrough et al., 2013) has caused a re-evaluation of the neurobiology of major depressive disorder. Although it is unclear whether ketamine could be safely adopted for general clinical practice (Krystal et al., 2013; Rush, 2013), ketamine's rapid efficacy highlights the importance of glutamatergic systems in major depression and at the same "
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    ABSTRACT: Following the discovery of the antidepressant properties of ketamine, there has been a recent resurgence in the interest in this NMDA receptor antagonist. Although detailed animal models of the molecular mechanisms underlying ketamine's effects have emerged, there are few MEG/EEG studies examining the acute subanesthetic effects of ketamine infusion in man. We recorded 275 channel MEG in two experiments (n = 25 human males) examining the effects of subanesthetic ketamine infusion. MEG power spectra revealed a rich set of significant oscillatory changes compared with placebo sessions, including decreases in occipital, parietal, and anterior cingulate alpha power, increases in medial frontal theta power, and increases in parietal and cingulate cortex high gamma power. Each of these spectral effects demonstrated their own set of temporal dynamics. Dynamic causal modeling of frontoparietal connectivity changes with ketamine indicated a decrease in NMDA and AMPA-mediated frontal-to-parietal connectivity. AMPA-mediated connectivity changes were sustained for up to 50 min after ketamine infusion had ceased, by which time perceptual distortions were absent. The results also indicated a decrease in gain of parietal pyramidal cells, which was correlated with participants' self-reports of blissful state. Based on these results, we suggest that the antidepressant effects of ketamine may depend on its ability to change the balance of frontoparietal connectivity patterns. In this paper, we found that subanesthetic doses of ketamine, similar to those used in antidepressant studies, increase anterior theta and gamma power but decrease posterior theta, delta, and alpha power, as revealed by magnetoencephalographic recordings. Dynamic causal modeling of frontoparietal connectivity changes with ketamine indicated a decrease in NMDA and AMPA-mediated frontal-to-parietal connectivity. AMPA-mediated connectivity changes were sustained for up to 50 min after ketamine infusion had ceased, by which time perceptual distortions were absent. The results also indicated a decrease in gain of parietal pyramidal cells, which was correlated with participants' self-reports of blissful state. The alterations in frontoparietal connectivity patterns we observe here may be important in generating the antidepressant response to ketamine. Copyright © 2015 the authors 0270-6474/15/3511695-13$15.00/0.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 08/2015; 35(33):11694-11706. DOI:10.1523/JNEUROSCI.0903-15.2015 · 6.34 Impact Factor
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    • "The glutamate N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has shown rapid antidepressant effects (e.g. within 24 h) in patients with treatment-resistant MDD (TRD) (Zarate et al. 2006; Mathew et al. 2012; Murrough, 2012; Murrough et al. 2013a, b, Lapidus et al. 2014; Wan et al. 2014) and bipolar depression (Diazgranados et al. 2010a, b, Zarate et al. 2012). Ketamine's rapid onset of therapeutic action makes it a potentially attractive therapeutic candidate for patients who require rapid treatment for suicidal thinking. "
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    ABSTRACT: Suicide is a devastating public health problem and very few biological treatments have been found to be effective for quickly reducing the intensity of suicidal ideation (SI). We have previously shown that a single dose of ketamine, a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist, is associated with a rapid reduction in depressive symptom severity and SI in patients with treatment-resistant depression. We conducted a randomized, controlled trial of ketamine in patients with mood and anxiety spectrum disorders who presented with clinically significant SI (n = 24). Patients received a single infusion of ketamine or midazolam (as an active placebo) in addition to standard of care. SI measured using the Beck Scale for Suicidal Ideation (BSI) 24 h post-treatment represented the primary outcome. Secondary outcomes included the Montgomery-Asberg Depression Rating Scale - Suicidal Ideation (MADRS-SI) score at 24 h and additional measures beyond the 24-h time-point. The intervention was well tolerated and no dropouts occurred during the primary 7-day assessment period. BSI score was not different between the treatment groups at 24 h (p = 0.32); however, a significant difference emerged at 48 h (p = 0.047). MADRS-SI score was lower in the ketamine group compared to midazolam group at 24 h (p = 0.05). The treatment effect was no longer significant at the end of the 7-day assessment period. The current findings provide initial support for the safety and tolerability of ketamine as an intervention for SI in patients who are at elevated risk for suicidal behavior. Larger, well-powered studies are warranted.
    Psychological Medicine 08/2015; DOI:10.1017/S0033291715001506 · 5.94 Impact Factor
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    • "However, ketamine-treated patients experienced dissociative side effects during the first 2 h post-infusion. A subsequent trial demonstrated ketamine's effectiveness in treatment-resistant MDD, which is defined as inadequate response to more than two antidepressants (Zarate et al., 2006). However, a single ketamine infusion was not long-lasting, with 35% of patients maintaining a significant antidepressant response for up to 1 week. "
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    ABSTRACT: A debilitating mental disorder, major depressive disorder is a leading cause of global disease burden. Existing antidepressant drugs are not adequate for the majority of depressed patients, and large clinical studies have demonstrated their limited efficacy and slow response onset. Growing evidence of low-dose ketamine's rapid and potent antidepressant effects offers strong potential for future antidepressant agents. However, ketamine has considerable drawbacks such as its abuse potential, psychomimetic effects, and increased oxidative stress in the brain, thus limiting its widespread clinical use. To develop superior antidepressant drugs, it is crucial to better understand ketamine's antidepressant mechanism of action. Recent preclinical studies indicate that ketamine's antidepressant mechanism involves mammalian target of rapamycin pathway activation and subsequent synaptogenesis in the prefrontal cortex, as well as glycogen synthase kinase-3 beta (GSK-3β) inactivation. Adjunct GSK-3β inhibitors, such as lithium, can enhance ketamine's efficacy by augmenting and prolonging its antidepressant effects. Given the potential for depressive relapses, lithium in addition to ketamine is a promising solution for this clinical issue.
    Frontiers in Neuroscience 08/2015; 9:249. DOI:10.3389/fnins.2015.00249 · 3.66 Impact Factor
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