Features of dissociation differentially predict antidepressant response to ketamine in treatment-resistant depression

Abstract

Background: Ketamine induces rapid and robust antidepressant effects, and many patients also describe dissociation, which is associated with antidepressant response. This follow-up study investigated whether antidepressant efficacy is uniquely related to dissociative symptom clusters.

Methods: Treatment-resistant patients with major depressive disorder (MDD) or bipolar disorder (BD) (n = 126) drawn from three studies received a single subanesthetic (0.5 mg/kg) ketamine infusion. Dissociative effects were measured using the Clinician-Administered Dissociative States Scale (CADSS). Antidepressant response was measured using the 17-item Hamilton Depression Rating Scale (HAM-D). A confirmatory factor analysis established the validity of CADSS subscales (derealization, depersonalization, amnesia), and a general linear model with repeated measures was fitted to test whether subscale scores were associated with antidepressant response.

Results: Factor validity was supported, with a root mean square error of approximation of .06, a comparative fit index of .97, and a Tucker-Lewis index of .96. Across all studies and timepoints, the depersonalization subscale was positively related to HAM-D percent change. A significant effect of derealization on HAM-D percent change was observed at one timepoint (Day 7) in one study. The amnesia subscale was unrelated to HAM-D percent change.

Limitations: Possible inadequate blinding; combined MDD/BD datasets might have underrepresented ketamine's antidepressant efficacy; the possibility of Type I errors in secondary analyses.

Conclusions: From a psychometric perspective, researchers may elect to administer only the CADSS depersonalization subscale, given that it was most closely related to antidepressant response. From a neurobiological perspective, mechanistic similarities may exist between ketamine-induced depersonalization and antidepressant response, although off-target effects cannot be excluded.

Keywords: Depression; Dissociation; Ketamine.

Conflict of interest statement

Declaration of Interest

Funding for this work was supported by the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH; ZIA MH002857; NIH Protocol 04-M-0222), by a NARSAD Independent Investigator Award to Dr. Zarate, and by a Brain and Behavior Mood Disorders Research Award to Dr. Zarate. Dr. Zarate is listed as a coinventor on a patent for the use of ketamine and its metabolites in major depression and suicidal ideation. Dr. Zarate is listed as a co-inventor on a patent for the use of (2R,6R)-hydroxynorketamine, (S)-dehydronorketamine, and other stereoisomeric dehydro and hydroxylated metabolites of (R,S)-ketamine metabolites in the treatment of depression and neuropathic pain. Dr. Zarate is listed as co-inventor on a patent application for the use of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and post-traumatic stress disorders; he has assigned his patent rights to the U.S. government but will share a percentage of any royalties that may be received by the government. All other authors have no conflict of interest to disclose, financial or otherwise.

Published by Elsevier B.V.

Figures

Figure 1. CADSS Derealization Subscale and Antidepressant Response to Ketamine

A statistically significant three-way interaction was observed between the CADSS Derealization subscale score, study, and time (F(4,208)=2.7, p=.03. Slope was significant only for the Ket-MOA study at Day 7 (B=−1.55, SE=0.65; t(204)=−2.37, p=.019). Predicted values from the linear mixed model are plotted; shaded areas represent the 95% confidence limits. Abbreviations: BD: bipolar disorder; CADSS, Clinician Administered Dissociative States Scale; HAM-D: Hamilton Depression Rating Scale; MOA: Mechanism of Action; B: unstandardized regression coefficient; SE: Standard Error

Figure 2. CADSS Depersonalization Subscale and Antidepressant Response to Ketamine

A main effect of CADSS Depersonalization subscale score was observed (t(118)=−2.07, p=.04; interactions with study and time were non-significant). Fit line was computed for visualization at Day 1 for KET-MOA. Shaded areas represent the 95% confidence limits. Abbreviations: CADSS, Clinician Administered Dissociative States Scale; HAM-D: Hamilton Depression Rating Scale; B: unstandardized regression coefficient; SE: Standard Error