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Cited by 284Treatment of Major DepressionElectroconvulsive Therapy StudiesTranscranial Magnetic Stimulation Studies

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

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Luckenbaugh, David A., Niciu, Mark J., Ionescu, Dawn F., Nolan, Neal M., Richards, Erica M., Brutsche, Nancy E., Guevara, Sara, Zarate, Carlos A.·2014·Journal of Affective Disorders
DOI 10.1016/j.jad.2014.02.017PMC PMC4065787
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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 230min and Days 1 and 7.Results Pearson correlations showed significant association between increased CADSS score at 40min and percent improvement with ketamine in HDRS at 230min (r=-0.35, p=0.007) and Day 7 (r=-0.41, p=0.01). Changes in YMRS or BPRS Positive Symptom score at 40min 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.

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Crossref · 10.1016/j.jad.2014.02.017

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  • Many patients describe psychedelic-induced peak or mystical experiences as being among the most meaningful events of their lives, and the intensity of these events correlates with therapeutic responses.

    “Many patients describe psychedelic-induced “peak” or “mystical” experiences as being among the most meaningful events of their lives, and the intensity of these events correlates with therapeutic responses (40, 220–226).”

    From Psychedelics and Other Psychoplastogens for Treating Mental Illness. (2021) · cites this paper as [225]

    The Results report that greater ketamine-induced dissociation correlated with improvement in depression at 230 minutes and Day 7. The paper does not describe peak or mystical experiences, patients ranking them among their most meaningful life events, or a correlation between the intensity of those experiences and therapeutic response; it measured dissociative side effects instead. The indexed passages provide no page numbers. (LLM, conf=0.86)

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  • The relationship between derealization and increased SV2A density observed here may be mediated by glutamate release.

    “Given the dose-response relationship between the glutamate surge, synaptogenesis and antidepressant response following ketamine administration 28,56,57 , it is possible that the relationship between derealization and increased SV2A density observed here is mediated by glutamate release.”

    From Imaging the effect of ketamine on synaptic density (SV2A) in the living brain (2022) · cites this paper as [56]

    The Discussion proposes that ketamine-enhanced glutamate release may contribute to dissociation, supporting the proposed mechanism in general. It does not examine derealization in relation to SV2A density or establish the cited sentence’s dose-response relationship among glutamate release, synaptogenesis, and antidepressant response. The SV2A observation is the citing authors’ own finding, not a result of this paper. (LLM, conf=0.85)

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  • The observed associations between antidepressant response, change in SV2A density, and symptoms of derealization could reflect target engagement (ketamine-induced glutamate release), leading to dissociative effects, a subsequent elicitation of synaptogenesis and resultant antidepressant response.

    “These associations could reflect target engagement (ketamine-induced glutamate release), leading to dissociative effects, a subsequent elicitation of synaptogenesis and resultant antidepressant response 28,56,57 .”

    From Imaging the effect of ketamine on synaptic density (SV2A) in the living brain (2022) · cites this paper as [56]

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  • Ketamine is a dissociogenic drug.

    “ketamine is a dissociogenic drug [130,131]”

    From Treatment of dissociative identity disorder: leveraging neurobiology to optimize success (2024) · cites this paper as [130]

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Research works printed but not linked: 1

  1. First M Spitzer RL Gibbon M Williams JBW 2002 Structured Clinical Interview for the DSM-IV-TR Axis I Disorders-Patient Edition Biometrics Research Department, New York State Psychiatric Institute New York

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Authors
Luckenbaugh, D. A., Niciu, M. J., Ionescu, D. F., Nolan, N. M., Richards, E. M., Brutsche, N. E., Guevara, S., & Zarate, C. A.
Affiliations
National Institutes of Health (US)
Corresponding author
Zarate, Carlos A.
ORCID
Venue
Journal of Affective Disorders
Publisher
Elsevier BV
Published
2014-04
Volume
159
Pages
56-61
ISSN
0165-0327 (ISSN-L)
DOI
10.1016/j.jad.2014.02.017
PMC
PMC4065787
OpenAlex
W2141217193
Cited by
283
References
35
Citations by year
2026: 14 · 2025: 15 · 2024: 31 · 2023: 25 · 2022: 24 · 2021: 25 · 2020: 25 · 2019: 16 · 2018: 25 · 2017: 17 · 2016: 22 · 2015: 27 · 2014: 15 · 2013: 1
FWCI
19.62
Type
journal article
Language
en
Open access
Locations
  • Journal of Affective Disorders (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Institute of Mental Health (ZIAMH002857, ZIAMH002927)
Topics
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Health Sciences › Medicine › Psychiatry and Mental health › Electroconvulsive Therapy Studies
  • Life Sciences › Neuroscience › Neurology › Transcranial Magnetic Stimulation Studies
Keywords
ketamine, antidepressant effects, dissociation, psychotomimetic side effects, major depressive disorder, bipolar disorder, treatment-resistant depression, NMDA receptor antagonists, dissociative states, hemodynamic changes
MeSH terms
Adult, Antidepressive Agents, Bipolar Disorder, Major Depressive Disorder, Dissociative Disorders, Female, Humans, Ketamine, Male, Middle Aged, Prospective Studies, Psychiatric Status Rating Scales, Treatment Outcome

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