Article

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: 13.75). 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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    • "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 · 5.43 Impact Factor
    • "It is unclear whether this is maintained following repeated ketamine infusions. Ketamine may need to be given repeatedly in the clinic, as its effects often do not last longer than one week (Berman et al., 2000; Zarate et al., 2006), and evidence for the feasibility of repeateddose ketamine to maintain antidepressant effects is lacking (aan het Rot et al., 2010; Sisti et al., 2014). Consequently, more research is required to examine the effects of multiple ketamine infusions. "
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    ABSTRACT: Ketamine is associated with rapid antidepressant efficacy but the biological mechanisms underpinning this effect are unclear. Serum brain-derived neurotrophic factor (sBDNF) is a potential circulating biomarker of treatment-resistant depression (TRD) and ketamine response but it is unclear if this is a common target of both ketamine and electroconvulsive therapy (ECT), the current gold standard for TRD. Moreover, the impact of multiple ketamine infusions on sBDNF has not yet been established. Thirty five TRD patients with a current DSM-IV diagnosis of recurrent depressive disorder received up to 12 ECT sessions (N=17) or up to three intravenous infusions of low-dose (0.5mg/kg) ketamine (N=18). Blood samples were taken over the course of the study for assessment of sBDNF. Symptom severity and response were monitored using the 17-item Hamilton Depression Rating Scale (HDRS). sBDNF was assessed in 20 healthy controls to allow comparison with TRD patients. As expected, sBDNF was lower in TRD patients at baseline compared to healthy controls. Ketamine and ECT treatment were both associated with significant reductions in depressive symptoms. However, sBDNF was significantly elevated only at one week following the first ketamine infusion in those classified as responders one week later. sBDNF was not elevated following subsequent infusions. ECT reduced depressive symptoms, as expected, but was not associated with an enhancement in BDNF. Patients continued with their psychotropic medications throughout this trial. SBDNF normalisation does not appear to be a prerequisite for symptomatic improvement in TRD following ketamine or ECT treatment. Copyright © 2015 Elsevier B.V. All rights reserved.
    Journal of Affective Disorders 07/2015; 186:306-311. DOI:10.1016/j.jad.2015.06.033 · 3.71 Impact Factor
    • "(R,S)-Ketamine (Ket) is a phencyclidine derivative that produces rapid and short-lived anesthesia with a wide margin of clinical safety (Domino 2010; Hirota and Lambert 2011); however, disturbing emergence reactions and dissociative and hallucinogenic effects have been reported following the use of (R,S)-Ket (White et al. 1982). Recent studies have shown that (R,S)-Ket is also an effective antidepressant agent, as illustrated by the work of Zarate et al. (2006), in which a single subanesthetic dose of the drug produced rapid antidepressant responses in patients with treatment-resistant major depressive disorder (MDD). While the use of (R,S)-Ket in the treatment of MDD and bipolar depression is an effective and increasingly popular therapeutic approach, its administration is also accompanied by dissociative side effects as measured by an increase in the Clinician-Administered Dissociative States Scale (CADSS) (Pomarol-Clotet et al. 2006; Zarate et al. 2012; Luckenbaugh et al. 2014). "
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    ABSTRACT: Patients with major depressive disorder receiving racemic ketamine, (R,S)-ketamine, experience transient increases in Clinician-Administered Dissociative States Scale (CADDS) scores and coincident drop in plasma D-serine levels. The results suggest that (R,S)-ketamine produces an immediate, concentration-dependent pharmacological effect on D-serine plasma concentrations. One potential source of this effect is the (R,S)-ketamine-induced inhibition of the alanine-serine-cysteine transporter (ASCT2), which regulates intracellular D-serine concentrations. In this study, we have tested this hypothesis by examining the effect of (S)- and (R)-ketamine on the ASCT2-mediated transport of D-serine in PC-12 and 1321N1 cells and primary neuronal cells in culture. Intracellular and extracellular D-serine levels were determined using capillary electrophoresis-laser induced fluorescence and liquid chromatography-mass spectrometry, respectively. Expression of ASCT2, Asc-1 and serine racemase was determined utilizing western blotting. Incubation with (S)-ketamine produced a concentration-dependent increase in intracellular D-serine levels and reduced extracellular D-serine accumulation. In contrast, (R)-ketamine decreased both the intracellular and extracellular D-serine levels. The contribution of ASCT2 and Asc-1 in ketamine-mediated D-serine transport was then assessed. Both the pharmacological inhibition of ASCT2 with benzyl-D-serine and ASCT2 gene knockdown mimicked the action of (S)-ketamine toward D-serine levels in PC-12 cells, while incubation with the Asc-1 agonist D-isoleucine reduced intracellular D-serine levels and increased extracellular D-serine accumulation. This response to D-isoleucine was not affected by benzyl-D-serine or (S)-ketamine. Primary cultures of rat neuronal cells expressed ASCT2 and were responsive to (S)-ketamine and benzyl-D-serine. Incubation with (S)-ketamine and (R)-ketamine increased the expression of monomeric serine racemase in all the studied cells, with (S)-ketamine having the greatest effect. The results indicate that (S)-ketamine decreases cellular export of D-serine via selective inhibition of ASCT2, and this could represent a possible source of dissociative effects observed with (R,S)-ketamine. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 07/2015; DOI:10.1111/bph.13239 · 4.99 Impact Factor
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