Ketamine's antidepressant efficacy is extended for at least four weeks in subjects with a family history of an alcohol use disorder

Abstract

Background: A single subanesthetic infusion of the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has rapid and potent antidepressant properties in treatment-resistant major depressive disorder (TRD). As a family history of an alcohol use disorder is a positive predictor of ketamine's antidepressant response and the strength of the association increases over time, we hypothesized that depressed subjects with a family history of an alcohol use disorder would have greater antidepressant durability and that riluzole would augment and/or extend ketamine's antidepressant efficacy.

Methods: Fifty-two TRD subjects received an open-label infusion of ketamine (0.5mg/kg over 40 minutes), and, four to six hours post-infusion, were randomized to either flexible-dose (100-200mg/day) riluzole or placebo in the following proportions: Family History Positive (FHP) riluzole (n = 10), FHP placebo (n = 9), Family History Negative (FHN) riluzole (n = 16), and FHN placebo (n = 17).

Results: FHP subjects randomized to placebo had a greater antidepressant response than FHN subjects; however, contrary to our initial hypothesis, there was no significant difference in antidepressant efficacy with riluzole. Although potentially underpowered, there was no difference in overall time-to-relapse based on randomization status (riluzole responders: n = 15, placebo responders: n = 17). Yet, time-to-relapse was longer in FHP placebo responders (n = 8) compared to FHN placebo responders (n = 9) with, again, no significant difference in time-to-relapse in FHP riluzole responders (n = 6) compared to FHN riluzole responders (n = 9).

Conclusions: Ketamine's extended antidepressant durability in FHP TRD should be considered in the design and analysis of ketamine depression trials.

Keywords: alcohol use disorder; family history; ketamine; major depressive disorder; riluzole.

Figure 1.

Ketamine’s antidepressant efficacy is improved for at least four weeks in treatment-resistant unipolar depressed subjects with a family history of an alcohol use disorder. (A) When randomized to placebo 4–6 hours after a single subanesthetic intravenous ketamine infusion, treatment-resistant unipolar depressed subjects with a family history of an alcohol use disorder displayed a greater antidepressant response over the next four weeks [group x time interaction: F(1,50) = 9.69, p = .003]. (B) When randomized to flexible-dose riluzole (100–200mg/day) 4–6 hours after a single subanesthetic intravenous infusion of ketamine, there was no statistically significant difference in antidepressant response based on family history status [group x time interaction: F(1,68) = .003, p = .95]. Abbreviations: FHP: family history positive; FHN: family history negative.

Figure 2.

Ketamine’s antidepressant efficacy is maintained in treatment-resistant unipolar depressed subjects with a family history of an alcohol use disorder. (A) Prior to stratification by family history status, in a Kaplan-Meier survival analysis, riluzole did not delay time-to-relapse in treatment-resistant MDD antidepressant responders (χ² = 3.73, p = .053). Response was defined as ≥50% MADRS improvement from baseline at any time point before 230 minute post-infusion, and relapse was defined as two consecutive days where patients had <25% improvement from baseline MADRS. (B) In the subgroup analysis, ketamine’s antidepressant response was extended in FHP patients randomized to placebo post–ketamine infusion. Abbreviations: FHP: family history positive; FHN: family history negative.