Do the dissociative side effects of ketamine mediate its antidepressant effects?

Abstract

Background The N-methyl-D-aspartate receptor antagonist ketamine has rapid antidepressant effects in major depression. Psychotomimetic symptoms, dissociation and hemodynamic changes are known side effects of ketamine, but it is unclear if these side effects relate to its antidepressant efficacy. Methods Data from 108 treatment-resistant inpatients meeting criteria for major depressive disorder and bipolar disorder who received a single subanesthetic ketamine infusion were analyzed. Pearson correlations were performed to examine potential associations between rapid changes in dissociation and psychotomimesis with the Clinician-Administered Dissociative States Scale (CADSS) and Brief Psychiatric Rating Scale (BPRS), respectively, manic symptoms with Young Mania Rating Scale (YMRS), and vital sign changes, with percent change in the 17-item Hamilton Depression Rating scale (HDRS) at 40 and 230 min and Days 1 and 7. Results Pearson correlations showed significant association between increased CADSS score at 40 min and percent improvement with ketamine in HDRS at 230 min (r= −0.35, p=0.007) and Day 7 (r=−0.41, p=0.01). Changes in YMRS or BPRS Positive Symptom score at 40 min were not significantly correlated with percent HDRS improvement at any time point with ketamine. Changes in systolic blood pressure, diastolic blood pressure, and pulse were also not significantly related to HDRS change. Limitations Secondary data analysis, combined diagnostic groups, potential unblinding. Conclusions Among the examined mediators of ketamine’s antidepressant response, only dissociative side effects predicted a more robust and sustained antidepressant. Prospective, mechanistic investigations are critically needed to understand why intra-infusion dissociation correlates with a more robust antidepressant efficacy of ketamine.

Randomised controlled trial of ketamine augmentation of electroconvulsive therapy to improve neuropsychological and clinical outcomes in depression (Ketamine-ECT study)

“…One retrospective study has found that intra-infusion dissociation predicts antidepressant response 4 hours and 7 days later. 171 The cognitive effects of ECT in our study were milder than might have been expected from the literature and it is possible that the now widespread use of a pulse width of 0.5 milliseconds for ECT in the UK results in less effect on cognition than 1-millisecond and 1.5-milliseconds pulse widths used historically (as has recently been proposed by others 171 ). Although studies have been carried out comparing ultra-brief-pulse (0.25-0.3 milliseconds) and brief-pulse (typically ≥ 1 millisecond) ECT, we are not aware of a direct comparison between 0.5 milliseconds and longer-duration brief-pulse stimuli; this may be indicated to ascertain the optimal range of the pulse width used to minimise cognitive effects while maintaining efficacy.…”

Temporal Dynamics of Antidepressant Ketamine Effects on Glutamine Cycling Follow Regional Fingerprints of AMPA and NMDA Receptor Densities

“…The transient psychometric effects are frequently found during the administration of ketamine and shortly afterwards (Luckenbaugh et al, 2014;Sos et al, 2013;Zarate et al, 2006). Therefore, measuring ketamine's effects only during or soon after its administration might be misleading, as it is hard to interpret whether findings reflect ketamine's acute dissociative effects or more specifically on antidepressant properties.…”

Ketamine for Depression: A Mixed-Methods Study

“…As noted, Luckenbaugh et al (2014) indicated that dissociative effects predicted a sustained antidepressant response. Subjects in this study who were experienced ketamine users received doses in accordance with the NIMH protocol that produced relatively mild dissociative symptoms, and most of these reported only minimal beneficial impact.…”