Intravenous Ketamine for Late-Life Treatment-Resistant Depression: A Pilot Study of Tolerability, Safety, Clinical Benefits, and Effect on Cognition

Abstract

Objective: Evidence-based treatment options for late-life treatment-resistant depression (TRD) are limited. Ketamine is a promising treatment for TRD; however, there is a paucity of data on its safety and efficacy in older adults.

Methods: In this pilot clinical trial, 25 adults aged ≥60 years with TRD received IV ketamine openly twice a week for 4 weeks; partial responders at the end of this acute phase were eligible to receive weekly infusions for 4 more weeks in a continuation phase. Acceptability, tolerability, and safety, including adverse and serious adverse events (AEs and SAEs), blood pressure changes, dissociation, craving, in addition to rates of depression response and remission were evaluated. The NIH Toolbox Cognitive Battery was used to assess specific measures of executive function (EF) and overall fluid cognition.

Results: Completion rates were 88% for the acute phase and 100% for the continuation phase. No AEs resulted in participant discontinuation, and there were no SAEs. Treatment-emergent elevation of blood pressure, dissociation, and craving were transient and did not result in any participant discontinuation. Depressive symptoms improved significantly and 48% of participants responded. During the acute phase, the EF measures and the fluid cognition composite score improved (Cohen's d = 0.61), and these improvements were sustained in the continuation phase.

Conclusion: This pilot study suggests that repeated IV ketamine infusions are well-tolerated and are associated with improvement in depression and EF in older adults with TRD. These promising findings need to be confirmed and extended in a larger randomized controlled trial.

Keywords: Treatment-resistant depression; cognition; geriatric; intravenous ketamine.

FIGURE 1.

Mean scores on the Clinician-Administered Dissociative States Scale (CADSS) before, during, and after each infusion in acute and continuation phases. CADSS scores were collected preinfusion, and 40 and 90 minutes after the start of the infusions.

FIGURE 2.

Montgomery-Asberg Depression Rating Scale (MADRS) scores trajectories in participants with less than 30% reduction and participants with 30% or greater MADRS reduction over time. (Left) Spaghetti plots of the trajectories of MADRS scores for participants with less than 30% MADRS score reduction between baseline and acute phase end. (Right) Spaghetti plots of the trajectories of MADRS score in those with 30% or greater MADRS reduction between baseline, acute phase end, and continuation phase end.

FIGURE 3.

Age-correct fluid cognition composite score trajectories in participants with less than 30% reduction and participants with 30% or greater MADRS reduction over time. (Left) Spaghetti plots of the trajectories of age-corrected fluid cognition composite scores for participants with less than 30% MADRS score reduction between baseline and acute phase end. (Right) Spaghetti plots of the trajectories of age-corrected fluid cognition composite score in those with 30% or greater MADRS reduction between baseline, acute phase end, and continuation phase end.