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.

Context Existing therapies for bipolar depression have a considerable lag of onset of action. Pharmacological strategies that produce rapid antidepressant effects—for instance, within a few hours or days—would have an enormous impact on patient care and public health. Objective To determine whether an N-methyl-d-aspartate–receptor antagonist produces rapid antidepressant effects in subjects with bipolar depression. Design A randomized, placebo-controlled, double-blind, crossover, add-on study conducted from October 2006 to June 2009. Setting Mood Disorders Research Unit at the National Institute of Mental Health, Bethesda, Maryland. Patients Eighteen subjects with DSM-IV bipolar depression (treatment-resistant). Interventions Subjects maintained at therapeutic levels of lithium or valproate received an intravenous infusion of either ketamine hydrochloride (0.5 mg/kg) or placebo on 2 test days 2 weeks apart. The Montgomery-Asberg Depression Rating Scale was used to rate subjects at baseline and at 40, 80, 110, and 230 minutes and on days 1, 2, 3, 7, 10, and 14 postinfusion. Main Outcome Measures Change in Montgomery-Asberg Depression Rating Scale primary efficacy measure scores. Results Within 40 minutes, depressive symptoms significantly improved in subjects receiving ketamine compared with placebo (d=0.52, 95% confidence interval [CI], 0.28-0.76); this improvement remained significant through day 3. The drug difference effect size was largest at day 2 (d=0.80, 95% CI, 0.55-1.04). Seventy-one percent of subjects responded to ketamine and 6% responded to placebo at some point during the trial. One subject receiving ketamine and 1 receiving placebo developed manic symptoms. Ketamine was generally well tolerated; the most common adverse effect was dissociative symptoms, only at the 40-minute point. Conclusion In patients with treatment-resistant bipolar depression, robust and rapid antidepressant effects resulted from a single intravenous dose of an N-methyl-d-aspartate antagonist. Trial Registration clinicaltrials.gov Identifier: NCT00088699

Background Currently, no pharmacological treatments for bipolar depression exist that exert rapid (within hours) antidepressant or antisuicidal effects. We previously reported that intravenous administration of the N-methyl-D-aspartate (NMDA) antagonist ketamine produced rapid antidepressant effects in patients with treatment-resistant bipolar depression. The present study sought to replicate this finding in an independent sample. Methods In this double-blind, randomized, crossover, placebo-controlled study, 15 subjects with DSM-IV bipolar I or II depression maintained on therapeutic levels of lithium or valproate received a single intravenous infusion of either ketamine hydrochloride (0.5 mg/kg) or placebo on two test days two weeks apart. The primary outcome measure was the Montgomery-Asberg Depression Rating Scale (MADRS), which was used to rate overall depressive symptoms at baseline, at 40, 80, 110, and 230 minutes post-infusion, and on Days 1, 2, 3, 7, 10, and 14 post-infusion. Results Within 40 minutes, depressive symptoms as well as suicidal ideation significantly improved in subjects receiving ketamine compared to placebo (d=0.89, 95% C.I. = 0.61–1.16 and 0.98, 95% C.I. = 0.64–1.33, respectively); this improvement remained significant through Day 3. Seventy-nine percent of subjects responded to ketamine and 0% responded to placebo at some point during the trial. The most common side effect was dissociative symptoms, which occurred only at the 40-minute time-point. Conclusion This study replicated our previous finding that patients with bipolar depression who received a single ketamine infusion experienced a rapid and robust antidepressant response. In addition, we found that ketamine rapidly improved suicidal ideation in these patients.

Objective-Suicidal ideation is a medical emergency, especially when severe. Little research has been done on pharmacological interventions that could address this problem. Ketamine, an Nmethyl-D-aspartate (NMDA) antagonist, has been reported to have antidepressant effects within hours. We examined the effects of a single dose of ketamine on suicidal ideation in subjects with treatment-resistant major depressive disorder (MDD).Method-Thirty-three subjects with DSM-IV-diagnosed MDD received a single open-label infusion of ketamine (0.5 mg/kg) and rated at baseline, 40, 80, 120, and 230 minutes post-infusion with the Scale for Suicide Ideation (SSI), the Montgomery-Asberg Depression Rating Scale (MADRS), the Hamilton Depression Rating Scale (HDRS), and the Beck Depression Inventory (BDI).Results-Suicidal ideation scores decreased significantly on the SSI as well as on the suicide subscales of other rating instruments within 40 minutes; these decreases remained significant through the first four hours post-infusion (p<.001). Ten subjects (30%) had a SSI score 4 at baseline, and all dropped below a score of 4 (nine by 40 minutes and one by 80 minutes). For those starting below a score of 4 on the SSI, only one reached a score of 4. Depression, anxiety, and hopelessness were significantly improved at all time points (p<.001).Conclusion-Suicidal ideation in the context of MDD improved within 40 minutes of a ketamine infusion and remained improved for up to four hours post-infusion. Future studies with ketamine in suicidal ideation are warranted due to its potential impact on public health.

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The N-methyl-D-aspartate antagonist ketamine has rapid antidepressant effects in patients with treatment-resistant major depression (TRD); these effects have been reported to last for 1 week in some patients. However, the extent and duration of this antidepressant effect over longer periods has not been well characterized under controlled conditions. Riluzole, a glutamatergic modulator with antidepressant and synaptic plasticity-enhancing effects, could conceivably be used to promote the antidepressant effects of ketamine. This study sought to determine the extent and time course of antidepressant improvement to a single-ketamine infusion over 4 weeks, comparing the addition of riluzole vs placebo after the infusion. Forty-two subjects (18-65) with TRD and a Montgomery-Asberg Depression Rating Scale (MADRS) score of ≥ 22 received a single intravenous infusion of ketamine (0.5 mg/kg). Four to six hours post-infusion, subjects were randomized to double-blind treatment with either riluzole (100-200 mg/day; n=21) or placebo (n=21) for 4 weeks. Depressive symptoms were rated daily. A significant improvement (P<0.001) in MADRS scores from baseline was found. The effect size of improvement with ketamine was initially large and remained moderate throughout the 28-day trial. Overall, 27% of ketamine responders had not relapsed by 4 weeks following a single ketamine infusion. The average time to relapse was 13.2 days (SE=2.2). However, the difference between the riluzole and placebo treatment groups was not significant, suggesting that the combination of riluzole with ketamine treatment did not significantly alter the course of antidepressant response to ketamine alone.

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