Replication of ketamine's antidepressant efficacy in bipolar depression: a randomized controlled add-on trial

Abstract

Background: Currently, no pharmacological treatments for bipolar depression exist that exert rapid (within hours) antidepressant or antisuicidal effects. We previously reported that intravenous administration of the N-methyl-D-aspartate antagonist ketamine produced rapid antidepressant effects in patients with treatment-resistant bipolar depression. The present study sought to replicate this finding in an independent sample.

Methods: In this double-blind, randomized, crossover, placebo-controlled study, 15 subjects with DSM-IV bipolar I or II depression maintained on therapeutic levels of lithium or valproate received a single intravenous infusion of either ketamine hydrochloride (.5 mg/kg) or placebo on 2 test days 2 weeks apart. The primary outcome measure was the Montgomery-Asberg Depression Rating Scale, which was used to rate overall depressive symptoms at baseline; at 40, 80, 110, and 230 minutes postinfusion; and on days 1, 2, 3, 7, 10, and 14 postinfusion.

Results: Within 40 minutes, depressive symptoms, as well as suicidal ideation, significantly improved in subjects receiving ketamine compared with placebo (d = .89, 95% confidence interval = .61-1.16, and .98, 95% confidence interval = .64-1.33, respectively); this improvement remained significant through day 3. Seventy-nine percent of subjects responded to ketamine and 0% responded to placebo at some point during the trial. The most common side effect was dissociative symptoms, which occurred only at the 40-minute time point.

Conclusions: This study replicated our previous finding that patients with bipolar depression who received a single ketamine infusion experienced a rapid and robust antidepressant response. In addition, we found that ketamine rapidly improved suicidal ideation in these patients.

Trial registration: ClinicalTrials.gov NCT00088699.

Figure 1

Change in MADRS, 17-item HDRS, and BDI scores over 2 weeks (n=15). Values are expressed as generalized least square means and standard errors for the Intent to Treat (ITT) analysis. *indicates p<0.05, ** p <0.01, *** p <0.001.

Figure 2

(A) Proportion of patients responding (50% improvement on MADRS) to ketamine and placebo from 40 minutes to Day 14 post-infusion. (B) Proportion of patients experiencing remission (MADRS <10) to ketamine and placebo from 40 minutes to Day 14 post-infusion.

Figure 3

Change in suicidal thoughts (suicide item from MADRS) over 2 weeks. Values are expressed as generalized least squares means and standard errors for the Intent to Treat (ITT) analysis. *indicates p <0.05, ** p <0.01, *** p <0.001.

Figure 4

Change in MADRS scores over 2 weeks by BPD subtype (I vs. II; n=15).