Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD)

Abstract

Numerous placebo-controlled studies have demonstrated the ability of ketamine, an NMDA receptor antagonist, to induce rapid (within hours), transient antidepressant effects when administered intravenously (IV) at subanesthetic doses (0.5mg/kg over 40 minutes). However, the optimal antidepressant dose remains unknown. We aimed to compare to active placebo the rapid acting antidepressant properties of a broad range of subanesthetic doses of IV ketamine among outpatients with treatment-resistant depression (TRD). A range of IV ketamine doses were compared to active placebo in the treatment of adult TRD over a 3-day period following a single infusion over 40 minutes. This was an outpatient study conducted across six US academic sites. Outpatients 18–70 years old with TRD, defined as failure to achieve a satisfactory response (e.g., less than 50% improvement of depression symptoms) to at least two adequate treatment courses during the current depressive episode. Following a washout period, 99 eligible subjects were randomly assigned to one of five arms in a 1:1:1:1:1 fashion: a single intravenous dose of ketamine 0.1 mg/kg (n=18), a single dose of ketamine 0.2 mg/kg (n=20), a single dose of ketamine 0.5 mg/kg (n=22), a single dose of ketamine 1.0 mg/kg (n=20), and a single dose of midazolam 0.045 mg/kg (active placebo) (n=19). The study assessments (HAM-D-6, MADRS. SDQ, PAS, CGI-S and CGI-I) were performed at Days 0, 1, 3 (endpoint), 5, 7, 14, and 30 to assess the safety and efficacy. The overall group*time interaction effect was significant for the primary outcome measure, the HAM-D-6. In post-hoc pairwise comparisons controlling for multiple comparisons standard- (0.5 mg/kg) and high-doses (1 mg/kg) of intravenous ketamine were superior to active placebo; a low-dose (0.1 mg/kg) was significant only prior to adjustment (p=0.02, p-adj=0.14, d=−0.82 at Day 1). Most of the interaction effect was due to differences at Day 1, with no significant adjusted pairwise differences at Day 3. This pattern generally held for secondary outcomes. The infusions of ketamine were relatively well tolerated compared to active placebo, except for greater dissociative symptoms and transient blood pressure elevations with the higher doses. Our results suggest that there is evidence for the efficacy of the 0.5 mg/Kg and 1.0 mg/Kg subanesthetic doses of IV ketamine and no clear or consistent evidence for clinically meaningful efficacy of lower doses of IV ketamine. Trial Registration: NCT01920555.

Efficacy of intravenous ketamine treatment in anxious versus nonanxious unipolar treatment-resistant depression

“…In order to assess the effect of anxious depression status at baseline on the acute antidepressant response to ketamine versus midazolam treatment, our a priori planned analyses focused on Days 1 and 3 outcome measures. To note, results from previous analyses showed that the difference in efficacy between ketamine and midazolam is most demonstrable at Day 1, therefore largely accounting for the 72‐hr hypothesized effect of ketamine (Fava et al., ).…”

“…To note, although analyzing baseline anxious status as a moderator of response to ketamine was a priori planned in the study protocol, the study was only powered to detect the main outcome (Fava et al., ), and therefore not powered to address this exploratory aim.…”

“…In order to assess the effect of anxious depression status at baseline on the acute antidepressant response to ketamine versus midazolam treatment, our a priori planned analyses focused on Days 1 and 3 We repeated the same type of analyses for the following outcome To note, although analyzing baseline anxious status as a moderator of response to ketamine was a priori planned in the study protocol, the study was only powered to detect the main outcome (Fava et al, 2018), and therefore not powered to address this exploratory aim.…”

“…Clomipramine and Nortriptyline); other antidepressants included Bupropion, Mirtazapine, Vortioxetine; HAMD6: sixitem Hamilton Rating Scale for Depression; MADRS: Montgomery-Asberg Depression Rating Scale; CGI-S: Clinical Global Impression of Severity Scale; P < 0.05, ** P < 0.005, *** P < 0.0005. outcome measures. To note, results from previous analyses showed that the difference in efficacy between ketamine and midazolam is most demonstrable at Day 1, therefore largely accounting for the 72-hr hypothesized effect of ketamine(Fava et al, 2018).In the case of HAMD6 on Day 1 as the outcome measure, we fit a linear mixed effects model in which HAMD6 score on Day 1 was the dependent variable, HAMD6 score at baseline was a covariate, and predictor variables were ANX (anxious depression, not anxious depression), GROUP (ketamine and midazolam), and their interaction terms. We included a random effect for SITE (six sites).…”

“…measures: HAMD6 on Day 3, MADRS on Day 3 (to note: in the trial design, MADRS was not performed on Day 1), and CGI-S on Days 1 and 3 postinfusion.In order to assess the effect of anxious depression status at baseline on the level of dissociative symptoms experienced by subjects who received ketamine treatment, we conducted two independent-samples t-tests, first including all subjects who received ketamine treatment and second including only subjects who received ketamine 0.5 and 1.0 mg/kg (due to these doses correlating significantly with higher levels of dissociative symptoms compared to placebo, as reported in the main paper;Fava et al, 2018). CADSS scores at 40 min postinfusion start (time at which the most significant level of dissociative symptoms was observed in ketamine vs. placebo, as reported in the main paper;Fava et al, 2018) was used as the dependent outcome variable.…”