COGNITIVE OUTCOMES FOLLOWING SERIAL KETAMINE INFUSIONS IN TREATMENT-RESISTANT BIPOLAR I/II DEPRESSION: RESULTS FROM A RANDOMIZED, MIDAZOLAM-CONTROLLED TRIAL

Background

Bipolar disorder is associated with significant cognitive impairment, particularly in memory, attention, processing speed, and executive functioning, which contributes to poor functional outcomes and reduced quality of life. Ketamine has been hypothesized to exert procognitive effects via neuroplastic mechanisms in addition to its antidepressant properties; however, evidence remains limited. Moreover, high doses and frequent use of ketamine have been associated with neurotoxicity. Critically, the cognitive effects of ketamine have not been systematically evaluated in bipolar depression, leaving its efficacy and safety in this population unclear.

Methods

Adults with treatment resistant bipolar I/II depression (TRBD; n=68) were randomized to receive four infusions over two weeks of either ketamine (0.5-0.75 mg/kg) or midazolam (0.02-0.03 mg/kg). Participants completed a comprehensive cognitive battery at baseline, Day 14, and Day 28, including the Digit Symbol Substitution Test (DSST), Trail Making Test Parts A and B (TMT-A/B), and California Verbal Learning Test–Second Edition (CVLT). Baseline impairment was defined as performance > 1.0 SD below ageadjusted normative means. Cognitive outcomes were analyzed using paired samples t-tests within treatment arms, baseline-adjusted ANCOVAs at Day 14 and Day 28, and linear mixed-effects models (LMMs). Subjective cognitive symptoms were assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS) item 6.

Results

At baseline, substantial cognitive impairment was observed across executive function/processing speed (TMT-B, n = 37; TMT-A, n = 29; DSST, n = 15) and verbal learning and memory (CVLT list B, n = 29; trials 1–5 total, n = 28; trial 1, n = 23; long-delay free recall, n = 16; short-delay free recall, n = 14). Within-group analyses showed significant improvement in the ketamine group on the DSST, TMT-A, and MADRS item 6 at Day 14 and Day 28, and on CVLT trial 1, trials 1–5 total, short-and long-delay free recall at Day 28 (all p < .020; Cohen’s d = .069–1.34). Only the TMT-B did not show improvement at either timepoint. In the midazolam group, significant improvements were observed on the DSST, TMT-A, and TMT-B at Day 14 and Day 28, and on MADRS item 6 and multiple CVLT indices (trial 1, trials 1–5 total, list B, short-and long-delay free recall) at Day 28 (all p < .028; d = .27–1.15). Between-group ANCOVAs revealed no significant differences in cognitive outcomes at Day 14 or Day 28, except for higher CVLT list B scores with midazolam at Day 28 (mean difference = 1.04; F(1, 53) = 4.55, p = .038, ηp² = .079) and lower MADRS item 6 scores with ketamine at Day 14 (mean difference = -.951; F(1, 58) = 10.16, p = .002, ηp² = .149). Consistent with this finding, the only significant group-by-time interaction in the LMMs was MADRS item 6 (F(1, 128.78) = 3.28, p = .041).

Significance

Despite high rates of baseline cognitive impairment, ketamine did not produce superior cognitive improvement relative to midazolam across objective cognitive domains. Cognitive changes over time were largely similar between groups, suggesting nonspecific or practice-related effects. Importantly, the absence of adverse cognitive effects across a broad neuropsychological battery supports the short-term cognitive safety and tolerability of repeated intravenous ketamine administration in TRBD.