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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    • "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.
    Psychological Medicine 10/2015; DOI:10.1017/S0033291715002159 · 5.94 Impact Factor
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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.
    Psychological Medicine 08/2015; -1:1-10. DOI:10.1017/S0033291715001506 · 5.94 Impact Factor
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    • "In sharp contrast to the slow onset of existing antidepressants, ketamine's fast-acting effects provide relief for MDD patients at risk for suicide. For example, ketamine infusions rapidly decreased explicit suicidal ideation in MDD patients within 24 h (Price et al., 2009), even when compared to midazolam (Price et al., 2014). In addition to MDD, ketamine is an effective antidepressant for bipolar-depressed patients as demonstrated by double-blind, saline placebo-controlled studies, in which patients had response rates of 70% or greater to ketamine (Diazgranados et al., 2010; Zarate et al., 2012b). "
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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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