Reconsidering "dissociation" as a predictor of antidepressant efficacy for esketamine.

For esketamine, a form of ketamine used for treatment-resistant depression, there is no clinically meaningful link between how dissociated a person feels during the drug experience and how much their depression improves. Analyzing data from 576 participants across two clinical trials, researchers measured dissociation with the Clinician-Administered Dissociative States Scale (CADSS) and depression with the Montgomery-Åsberg Depression Rating Scale (MADRS). A statistical model found no significant interaction between dissociation and antidepressant effect over four weeks. A separate analysis showed that each additional point on the dissociation scale on day 1 was associated with a very small 0.

Study at a glance

Abstract

The relationship between subjective drug experience and antidepressant outcomes for ketamine derivatives is poorly understood but of high clinical relevance. Esketamine is the patented (S)-enantiomer of ketamine and has regulatory approval for psychiatric applications. We examined the relationship between acute dissociation, as measured by the Clinician-Administered Dissociative States Scale (CADSS), and antidepressant efficacy, as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS), for esketamine across the 4-week induction phase of treatment. This post hoc analysis combined data (N = 576) from the TRANSFORM-1 and TRANSFORM-2 clinical trials of esketamine for treatment-resistant depression. Linear mixed models were performed using total MADRS score as the outcome variable with the following independent variables: baseline MADRS score, treatment condition × time interaction, and CADSS × time interaction. To assess whether initial dissociation predicted rapid antidepressant benefit with esketamine, a separately planned regression was performed with day 2 MADRS as the outcome variable with the following dependent variables: baseline MADRS, treatment condition, and day 1 CADSS. The linear mixed model did not show any effect of a CADSS × time interaction (p = 0.7). Looking solely at the effect of day 1 CADSS on day 2 MADRS revealed that each additional CADSS point was associated with a - .04 [95% CI - .08, - .002] (p = .04) decrease in MADRS score. We found no evidence of a clinically significant positive or negative association between dissociation and antidepressant effect for esketamine. Our findings suggest that subsequent inquiry in this area will benefit from improved characterization of drug experiences relevant to therapeutic outcomes.