title: A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression.
abstract: BACKGROUND
  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.
  
  
  METHODS
  A randomized, placebo-controlled, double-blind, crossover, add-on study conducted from October 2006 to June 2009.
  
  
  METHODS
  Mood Disorders Research Unit at the National Institute of Mental Health, Bethesda, Maryland. Patients Eighteen subjects with DSM-IV bipolar depression (treatment-resistant).
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Experimental Therapeutics, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Diazgranados
authors.forename: Lobna
authors.initials: L
authors.lastname: Ibrahim
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Brutsche
authors.forename: Andrew
authors.initials: A
authors.lastname: Newberg
authors.forename: Phillip
authors.initials: P
authors.lastname: Kronstein
authors.forename: Sami
authors.initials: S
authors.lastname: Khalife
authors.forename: William A
authors.initials: WA
authors.lastname: Kammerer
authors.forename: Zenaide
authors.initials: Z
authors.lastname: Quezado
authors.forename: David A
authors.initials: DA
authors.lastname: Luckenbaugh
authors.forename: Giacomo
authors.initials: G
authors.lastname: Salvadore
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Machado-Vieira
authors.forename: Husseini K
authors.initials: HK
authors.lastname: Manji
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Zarate
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001714:Bipolar Disorder / Q000175:diagnosis / Q000188:drug therapy* / Q000523:psychology; D039721:Diagnostic and Statistical Manual of Mental Disorders; D004311:Double-Blind Method; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007649:Ketamine / Q000627:therapeutic use*; D018020:Lithium Compounds / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors; D010919:Placebos; D011569:Psychiatric Status Rating Scales / Q000706:statistics & numerical data; D016896:Treatment Outcome; D014635:Valproic Acid / Q000627:therapeutic use
chemical_list: D018691:Excitatory Amino Acid Antagonists; D018020:Lithium Compounds; D010919:Placebos; D014635:Valproic Acid; D016202:N-Methylaspartate; D007649:Ketamine