A Randomized Add-on Trial of an N-methyl-d-aspartate Antagonist in Treatment-Resistant Bipolar Depression

By N. Diazgranados, Lobna A Ibrahim, N. Brutsché, Andrew R Newberg, Phillip Kronstein, S. Khalifé, W. Kammerer, Z. Quezado, D. Luckenbaugh, G. Salvadore and 3 more. Archives of General Psychiatry, 2010

966 citations recorded by the source corpus.

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

Subfields: Biological Psychiatry, Pharmacology, Psychiatry and Mental health

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Citations in the corpus

Replication of Ketamine’s Antidepressant Efficacy in Bipolar Depression: A Randomized Controlled Add-on Trial (2012, methodology): “pression who were concomitantly receiving either lithium or valproate (4).”
Brain-Derived Neurotrophic Factor and Neuropsychiatric Disorders (2012, background): “Recent evidence has suggested that ketamine, a well known anesthetic with NMDA receptor antagonist activity, is effective in very low doses for treatment of both MDD (Berman et al., 2000; Zarate et al., 2006; Price et al., 2009) and BD (Diazgranados et al., 2010).”
Towards a glutamate hypothesis of depression (2011, background): “…been shown at subanesthetic doses to induce rapid (within 24 h) antidepressant effects that are sustained for at least several days after a single infusion, in at least four blinded pilot clinical trials (Berman et al., 2000; Diazgranados et al., 2010; Valentine et al., 2011; Zarate et al., 2006).”
NMDAR inhibition-independent antidepressant actions of ketamine metabolites (2016, neutral): “ketamine studies: 238 → 125 (ketamine); 224 → 125 (norketamine); 222 → 177 (dehydronorketamine); 240 → 125 (HNK); 254 → 151 (HK) and (R,S)-d2-ketamine studies: 240 → 125 (d2-ketamine); 226 → 125 (d2-norketamine); 223 → 178 (ddehydronorketamine); 241 → 125 (d-(2,6)-HNK); 242-125 (d2-(2,5)-HNK);(d2-(2”
Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression: A Randomized Clinical Trial (2017, neutral): “Dizziness 1 (3) 4 (21) 8 (40) 8 (47) 20 (36)”
Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2013. (2013, background): “A two-week, crossover RCT assessing adjunctive ketamine infusion in patients with treatmentresistant bipolar depression identified a robust early antidepressant effect (within 40 min), with improvement remaining significant versus placebo through day three (level 2) (111).”