A Randomized Add-on Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Bipolar Depression
This double-blind, placebo-controlled, randomised study (n=18) with those suffering from bipolar depression (BD; treatment-resistant) found that ketamine (35mg/70kg; 2x 2w apart) produced anti-depressant effects as measured on the MADRS scale. The effects were found immediately (40 minutes) and lasted up to three days.
Authors
- Carlos Zarate
- David Luckenbaugh
- Nancy Elizabeth Brutsche
Published
Abstract
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.
Research Summary of 'A Randomized Add-on Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Bipolar Depression'
Introduction
Bipolar disorder (BPD) remains difficult to treat pharmacologically in part because most available agents were developed for other illnesses and because the neurobiology of bipolar depression is incompletely understood. Recent lines of evidence implicate glutamatergic dysfunction—particularly abnormalities of the NMDA‑receptor complex—in BPD. Postmortem studies report altered NMDA complexes, genetic associations have been observed for GRIN1 and GRIN2B subunits, and glutamatergic modulators such as riluzole show antidepressant effects and influence AMPA receptor trafficking. Preclinical data and clinical work in major depressive disorder also indicate that NMDA antagonists can produce rapid antidepressant effects within hours. Diazgranados and colleagues designed a proof‑of‑concept trial to test whether directly targeting the NMDA receptor with a single intravenous infusion of ketamine would produce a rapid antidepressant response in patients with treatment‑resistant bipolar I or II depression. The primary aim was to determine efficacy and safety of a 0.5 mg/kg ketamine infusion, given as an add‑on to therapeutic lithium or valproate, with measurement of depressive symptoms over minutes to 14 days postinfusion.
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Study Details
- Study Typeindividual
- Journal
- Compounds
- Topics
- Authors
- APA Citation
Diazgranados, N., Ibrahim, L., Brutsche, N. E., Newberg, A., Kronstein, P., Khalife, S., Kammerer, W. A., Quezado, Z., Luckenbaugh, D. A., Salvadore, G., Machado-Vieira, R., Manji, H. K., & Zarate, C. A. (2010). A Randomized Add-on Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Bipolar Depression. Archives of General Psychiatry, 67(8), 793. https://doi.org/10.1001/archgenpsychiatry.2010.90
References (1)
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