Research paperFeatures of dissociation differentially predict antidepressant response to ketamine in treatment-resistant depression
Introduction
The glutamatergic modulator ketamine is a U.S. Food and Drug Administration (FDA)-approved anesthetic. Distinct from traditional anesthetics, ketamine has been called a “dissociative anesthetic” due to the occurrence of dissociative symptoms (Sleigh et al., 2014). Dissociation can be loosely defined as a detachment from reality and manifests across a spectrum of severity. Pathological dissociation can include depersonalization (detachment from self), derealization (detachment from surroundings), amnesia and, in more severe, persistent manifestations, fugue states and dissociative identity disorder. At typical clinical doses, ketamine-induced dissociation is mild to moderate in severity and transient in duration, with patients returning to their premorbid mental state within hours of administration. Ketamine is thought to derive its anesthetic, psychotomimetic, and dissociative properties from noncompetitive, high-affinity antagonism at the N-methyl-D-aspartate (NMDA) receptor (MacDonald and Nowak, 1990).
A single, subanesthetic-dose ketamine infusion has repeatedly been demonstrated to reduce depressive symptoms in a matter of hours (Berman et al., 2000, Diazgranados et al., 2010, Ibrahim et al., 2012b, Murrough et al., 2013, Valentine et al., 2011, Zarate et al., 2006). NMDA receptor antagonism has been proposed as an initiating molecular event in ketamine's antidepressant effects (Maeng and Zarate, 2007), although recent preclinical evidence supports non-NMDA receptor-mediated antidepressant properties of the ketamine metabolite (2R,6R)-hydroxynorketamine (Zanos et al., 2016); as predicted in animal models, the latter is not associated with clinically problematic side effects such as psychomotor agitation, prepulse inhibition, and addictive-like behaviors (Green and Johnson, 1990, Zanos et al., 2016). While other NMDA receptor antagonists with lower and/or more specific affinities have demonstrated antidepressant efficacy without psychotomimetic or dissociative side effects (Ibrahim et al., 2012a, Zarate et al., 2013), these other NMDA receptor antagonists generally have much less robust and sustained antidepressant effects than ketamine; it is presently unclear whether this represents qualitative and/or quantitative differences at the receptor (Aan Het Rot et al., 2012, Zanos et al., 2016).
The relationship between ketamine's psychoactive side effects and antidepressant response has been explored in several studies. A study of 10 subjects with treatment-resistant major depressive disorder (MDD) found no association between maximum change in dissociative symptoms (as measured by the Clinician-Administered Dissociative States Scale (CADSS)) and change in depressive symptom scores (as measured by the Hamilton Depression Rating Scale (HAM-D)) in response to a single, subanesthetic-dose ketamine infusion (Valentine et al., 2011). Another study of 27 depressed hospitalized patients found a correlation between antidepressant response (as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS)) and psychotomimetic symptoms (as measured by the Brief Psychiatric Rating Scale (BPRS)) seven days post-ketamine infusion (Sos et al., 2013). Finally, a previous study from our laboratory reported that increased dissociative symptoms—but not psychotomimetic, hypomanic, or sympathomimetic symptoms—correlated with antidepressant response to ketamine at 230 min and at seven days post-ketamine infusion in 108 treatment-resistant hospitalized inpatients with either MDD or bipolar disorder (BD) (Luckenbaugh et al., 2014).
These conflicting findings prompted the present investigation into the relationship between ketamine-induced dissociative symptoms and antidepressant efficacy. This follow-up study uses a larger sample (n = 126, inclusive of the previous sample (Luckenbaugh et al., 2014)) and explores empirically validated subdimensions of dissociation for the first time. We hypothesized that increased dissociative symptoms would predict improvement in depressive symptom scores after ketamine infusion, but that subdimensions of dissociation, as derived by Bremner and colleagues (Bremner et al., 1998), would uniquely predict antidepressant response.
Section snippets
Participants and procedures
Data from 126 treatment-resistant depressed patients were analyzed (18–65 years old; 84 MDD, 42 BD). Patient data were obtained from one of three studies, colloquially identified as Ketamine-Bipolar (Ket-BD, n = 39) (Diazgranados et al., 2010, Zarate et al., 2012), Ketamine-Riluzole (Ket-Riluzole, n = 52) (Ibrahim et al., 2012b), or Ketamine-MOA (Ket-MOA, n = 35) (Nugent et al., in press) (Clinical Trials Identifier: NCT0088699; NIH Protocol 04-M-0222, substudies 2, 3, and 4, respectively). All
Characterization of sample
Participant demographics are shown in Table 1. Several demographic features differed significantly across studies; partially to account for this fact, study was entered as a covariate in all analyses.
Factor validity of the CADSS subscales
Factor validity of the CADSS subscales was evaluated using the 40-minute data (n = 126). The three-factor model was a good fit to the data, with a Root Mean Square Error of Approximation (RMSEA) of .06 (95% CI: .042 – .077), a Comparative Fit Index (CFI) of .97, and a Tucker-Lewis Index of .96.
Discussion
The present study extends previous work from our laboratory investigating ketamine-induced dissociation and antidepressant response (Luckenbaugh et al., 2014). In the initial report, intra-infusion dissociation positively correlated with antidepressant response to ketamine at two post-infusion timepoints: 230 min and Day 7; however, the previous analysis did not address whether specific dimensions of dissociation were uniquely related to antidepressant response. Using a larger sample and a
Acknowledgements
The authors thank the 7SE research unit and staff for their support. Ioline Henter (NIMH) provided invaluable editorial assistance.
Role of funding source
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. These agencies had no further role in study design; in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit
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2022, Journal of Affective DisordersCitation Excerpt :In addition to documenting temporal differences between dissociation, side effects and treatment outcome, these findings add to the complex picture emerging on the role of dissociation in ketamine treatment (Luckenbaugh et al., 2014; Valentine et al., 2011). The interplay between baseline severity, non-dissociative side effects, and dissociation reported here is an important area for future research and clinical practice and adds to findings that highlight the role of individual differences (Mello et al., 2021), timing of dissociation (Niciu et al., 2018), and durability of the treatment (Pennybaker et al., 2017). While this study demonstrates the promising potential of KAT for treating anxiety and depression and using telehealth for overcoming treatment access barriers and ensuring safety through remote monitoring, there are limitations of this study.