A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression

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.

Trial registration: ClinicalTrials.gov NCT00088699.

Figure 1

Enrollment, randomization, withdrawals, and completion of the 2 treatment phases (n=18).

Figure 2

Change in depression scale scores during 2 weeks in patients with bipolar disorder given placebo and ketamine (n=18). Values are expressed as generalized least-square means and standard errors for the intent-to-treat analysis. BDI indicates Beck Depression Inventory; HAM-D, 17-item Hamilton Scale for Depression; MADRS, Montgomery-Asberg Depression Rating Scale; *P<.001; †P<.01; and ‡P<.05.

Figure 3

Proportion of responders and remitters after ketamine or placebo infusion by Montgomery-Asberg Depression Rating Scale (MADRS) score. A, Proportion of responders (50% improvement on MADRS) from 40 minutes to day 14 postinfusion (n=18). B, Proportion of remitters (MADRS score <10) from 40 minutes to day 14 postinfusion (n=18).

Figure 4

Change in psychiatric scale scores in patients with bipolar disorder given placebo and ketamine (n=18). Values are expressed as generalized least-square means and standard errors for the intent-to-treat analysis. BPRS indicates Brief Psychiatric Rating Scale; CADSS, Clinician Administered Dissociative Scale; YMRS, Young Mania Rating Scale; *P<.05; †P<.01; and ‡P<.001.