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


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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    • "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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    • "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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    • "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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