EVALUATING THE ASSOCIATION BETWEEN ANTIDEPRESSANT EFFICACY AND DISSOCIATION WITH KETAMINE IN TREATMENT-RESISTANT BIPOLAR DEPRESSION (TRBD)

Background

Intravenous (IV) ketamine is associated with rapid and robust antidepressant effects at sub-anesthetic doses for treatment-resistant depression (TRD). Ketamine causes variable dissociative effects, creating a wide spectrum of “psychedelic experience” intensity between patients. However, evidence to date investigating whether this mind-altering experience is required for clinical benefits has been mixed and underpowered, leaving this research question largely understudied. There has been minimal research on the role of dissociation with ketamine in bipolar disorder specifically.

Methods

We pooled data from two unpublished clinical trials (both recently completed by our group) including adults with treatment-resistant bipolar depression (TRBD) receiving an acute course of ketamine treatment (four infusions over two weeks). Data was pooled from two multi-site clinical trials; a randomized, midazolam-controlled study (ClinicalTrials.gov: NCT05004896; n = 33 in ketamine arm), and a single-arm, open-label study (ClinicalTrials.gov: NCT05339074; n = 20 in the ketamine arm), to examine the correlation between the intensity of dissociation and antidepressant efficacy. Antidepressant efficacy was evaluated as a change in depression severity between baseline and after four infusions (Day 14) using the Montgomery-Åsberg Depression Rating Scale (MADRS). Assessment of dissociation occurred immediately after the first infusion using the Clinician-Administered Dissociative States Scale (CADSS).

Results

Depression severity decreased over time, with a mean MADRS score reduction of 10.8 points (95% CI: -8.3 to -13.4; p < 0.001) from a baseline mean of 30.7 (± 6.5) in the ketamine groups (pooled n = 53). The mean CADSS score at the peak of infusion and 20minutes post-infusion was 18.8 (± 13.7) and 0.8 (± 1.5), respectively. Linear regression analysis showed no significant correlation between peak CADSS scores and change in MADRS (F (1,51) = 0.024, p = 0.88), with dissociation accounting for only 1.3% of the explained variability in MADRS change.

Conclusion

As one of the first studies to evaluate ketamine’s dissociative symptoms in bipolar disorder, with data from the largest randomized clinical trial evaluating ketamine in this population to date, we found the intensity of dissociative effects did not predict antidepressant response. As our findings suggest that ketamine’s clinical benefits may not depend on a meaningful psychedelic experience, these results can provide reassurance to patients who do not experience strong dissociative effects. Moreover, further research can lead to the engineering of novel ketamine-like treatments that minimize psychoactive side effects for improved tolerability.