A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression.
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.
Diazgranados
Nancy
N
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.
Ibrahim
Lobna
L
Brutsche
Nancy E
NE
Newberg
Andrew
A
Kronstein
Phillip
P
Khalife
Sami
S
Kammerer
William A
WA
Quezado
Zenaide
Z
Luckenbaugh
David A
DA
Salvadore
Giacomo
G
Machado-Vieira
Rodrigo
R
Manji
Husseini K
HK
Zarate
Carlos A
CA
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
D018691:Excitatory Amino Acid Antagonists; D018020:Lithium Compounds; D010919:Placebos; D014635:Valproic Acid; D016202:N-Methylaspartate; D007649:Ketamine