Price RB, Nock MK, Charney DS, Mathew SJ. Effects of intravenous ketamine on explicit and implicit measures of suicidality in treatment-resistant depression. Biol Psychiatry 66: 522-526

Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, USA.
Biological psychiatry (Impact Factor: 10.26). 06/2009; 66(5):522-6. DOI: 10.1016/j.biopsych.2009.04.029
Source: PubMed


Intravenous ketamine has shown rapid antidepressant effects in early trials, making it a potentially attractive candidate for depressed patients at imminent risk of suicide. The Implicit Association Test (IAT), a performance-based measure of association between concepts, may have utility in suicide assessment.
Twenty-six patients with treatment-resistant depression were assessed using the suicidality item of the Montgomery-Asberg Depression Rating Scale (MADRS-SI) 2 hours before and 24 hours following a single subanesthetic dose of intravenous ketamine. Ten patients also completed IATs assessing implicit suicidal associations at comparable time points. In a second study, nine patients received thrice-weekly ketamine infusions over a 12-day period.
Twenty-four hours after a single infusion, MADRS-SI scores were reduced on average by 2.08 points on a 0 to 6 scale (p < .001; d = 1.37), and 81% of patients received a rating of 0 or 1 postinfusion. Implicit suicidal associations were also reduced following ketamine (p = .003; d = 1.36), with reductions correlated across implicit and explicit measures. MADRS-SI reductions were sustained for 12 days by repeated-dose ketamine (p < .001; d = 2.42).
These preliminary findings support the premise that ketamine has rapid beneficial effects on suicidal cognition and warrants further study.

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Available from: Matthew K Nock, Mar 28, 2014
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    • "So, rapid relief from fatigue is essential to attain full remission from depression. The rapid antidepressant effect of a noncompetitive glutamate N-methyl-D-aspartate (NMDA) receptor antagonist, such as a low dose ketamine, is well documented in individuals with MDD, even those with treatment-resistant depressive conditions (Berman et al., 2000;Price et al., 2009;Zarate et al., 2006). Ketamine's rapid anti-depressant effects are believed to be caused by disinhibiting gamma aminobutyric acid (GABA) inputs thus enhancing the firing rate of glutamatergic neurons, increasing presynaptic release of glutamate, and consequently increasing extracellular levels of glutamate which favors α-amino-3-hydroxy-5-methyl-4-iso- xazolepropionic acid receptors (AMPAR) over NMDA receptors (Diazgranados et al., 2010;Machado-Vieira et al., 2009;Zarate et al., 2006). "
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    ABSTRACT: Background: Fatigue is a multidimensional condition that is difficult to treat with standard monoaminergic antidepressants. Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist produces rapid and robust improvements in depressive symptoms in treatment-resistant depression. However, there is a dearth of literature examining the anti-fatigue effects of ketamine. We hypothesize that ketamine will rapidly improve fatigue symptoms in treatment-resistant depressed patients. Methods: This is an exploratory analysis of data obtained from two double-blind, randomized, placebo-controlled, crossover trials. A total of 36 participants with treatment-resistant bipolar I or II disorder in a depressive episode (maintained on therapeutic levels of lithium or valproate) received a single infusion of ketamine hydrochloride intravenously (0.5mg/kg over 40min) or placebo. A post-hoc analysis compared fatigue scores on ketamine vs. placebo at 10 time points from baseline through 14 days post-treatment using the National Institute of Health-Brief Fatigue Inventory. Results: A linear mixed model showed that ketamine significantly lowered fatigue scores compared to placebo from 40min post-treatment to Day 14 with the exception of Day 7. The largest difference in anti-fatigue effects between placebo and ketamine was at day 2 (d=0.58, p<0.05). The effect remained significant after controlling for changes in non-fatigue depressive symptoms. Limitation: The retrospective nature and a small sample size are study limitations. Conclusions: Ketamine rapidly improved fatigue relative to placebo in a group of individuals with treatment-resistant bipolar depression. NMDAR is a glutamate receptor; hence, glutamate may represent a valuable target to study the clinical efficacy of new anti-fatigue approaches in multiple disorders.
    Full-text · Article · Jan 2016 · Journal of Affective Disorders
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    • "Moreover, the dose was fixed at 10 mg/day and the long-term effect of ketamine cannot be evaluated in this study. Second, similar to most studies (Zarate et al. 2006; Price et al. 2009; aan het Rot et al. 2010; Diazgranados et al. 2010; Ibrahim et al. 2011), the sample size (n = 30) was relatively small in this study. Therefore our results are preliminary and need to be replicated in future studies with a large sample size. "
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    ABSTRACT: Background: While oral antidepressants reach efficacy after weeks, single-dose intravenous (i.v.) ketamine has rapid, yet time-limited antidepressant effects. We aimed to determine the efficacy and safety of single-dose i.v. ketamine augmentation of escitalopram in major depressive disorder (MDD). Method: Thirty outpatients with severe MDD (17-item Hamilton Rating Scale for Depression total score ⩾24) were randomized to 4 weeks double-blind treatment with escitalopram 10 mg/day+single-dose i.v. ketamine (0.5 mg/kg over 40 min) or escitalopram 10 mg/day + placebo (0.9% i.v. saline). Depressive symptoms were measured using the Montgomery-Asberg Depression Rating Scale (MADRS) and the Quick Inventory of Depressive Symptomatology - Self-Report (QIDS-SR). Suicidal ideation was evaluated with the QIDS-SR item 12. Adverse psychopathological effects were measured with the Brief Psychiatric Rating Scale (BPRS)-positive symptoms, Young Mania Rating Scale (YMRS) and Clinician Administered Dissociative States Scale (CADSS). Patients were assessed at baseline, 1, 2, 4, 24 and 72 h and 7, 14, 21 and 28 days. Time to response (⩾50% MADRS score reduction) was the primary outcome. Results: By 4 weeks, more escitalopram + ketamine-treated than escitalopram + placebo-treated patients responded (92.3% v. 57.1%, p = 0.04) and remitted (76.9% v. 14.3%, p = 0.001), with significantly shorter time to response [hazard ratio (HR) 0.04, 95% confidence interval (CI) 0.01-0.22, p < 0.001] and remission (HR 0.11, 95% CI 0.02-0.63, p = 0.01). Compared to escitalopram + placebo, escitalopram + ketamine was associated with significantly lower MADRS scores from 2 h to 2 weeks [(peak = 3 days-2 weeks; effect size (ES) = 1.08-1.18)], QIDS-SR scores from 2 h to 2 weeks (maximum ES = 1.27), and QIDS-SR suicidality from 2 to 72 h (maximum ES = 2.24). Only YMRS scores increased significantly with ketamine augmentation (1 and 2 h), without significant BPRS or CADSS elevation. Conclusions: Single-dose i.v. ketamine augmentation of escitalopram was safe and effective in severe MDD, holding promise for speeding up early oral antidepressant efficacy.
    Full-text · Article · Oct 2015 · Psychological Medicine
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    • "Previous reports have suggested that ketamine may have rapid anti-SI effects. In two initial analyses of the effects of ketamine on levels of SI in patients with TRD, Diazgranados et al. (2010a,b) and Price et al (2009) both reported rapid reductions in SI when ketamine was administered in an open-label manner. A prospective open-label study conducted in an emergency department setting demonstrated long-lasting reductions in SI up to 10 days following a single ketamine infusion (Larkin & Beautrais, 2011). "
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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.
    Full-text · Article · Aug 2015 · Psychological Medicine
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