Prolonged ketamine infusion modulates limbic connectivity and induces sustained remission of treatment-resistant depression
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Ketamine produces a rapid antidepressant response in over 50% of adults with treatment-resistant depression. A long infusion of ketamine may provide durable remission of depressive symptoms, but the safety, efficacy, and neurobiological correlates are unknown. In this open-label, proof-of-principle study, adults with treatment-resistant depression (N = 23) underwent a 96-h infusion of intravenous ketamine (0.15 mg/kg/h titrated toward 0.6 mg/kg/h). Clonidine was co-administered to reduce psychotomimetic effects. We measured clinical response for 8 weeks post-infusion. Resting-state functional magnetic resonance imaging was used to assess functional connectivity in patients pre- and 2 weeks post-infusion and in matched non-depressed controls (N = 27). We hypothesized that responders to therapy would demonstrate response-dependent connectivity changes while all subjects would show treatment-dependent connectivity changes. Most participants completed infusion (21/23; mean final dose 0.54 mg/kg/h, SD 0.13). The infusion was well tolerated with minimal cognitive and psychotomimetic side effects. Depressive symptoms were markedly reduced (MADRS 29 ± 4 at baseline to 9 ± 8 one day post-infusion), which was sustained at 2 weeks (13 ± 8) and 8 weeks (15 ± 8). Imaging demonstrated a response-dependent decrease in hyperconnectivity of the subgenual anterior cingulate cortex to the default mode network, and a treatment-dependent decrease in hyperconnectivity within the limbic system (hippocampus, amygdala, medial thalamus, nucleus accumbens). In exploratory analyses, connectivity was increased between the limbic system and frontal areas, and smaller right hippocampus volume at baseline predicted larger MADRS change. A single prolonged infusion of ketamine provides a tolerated, rapid, and sustained response in treatment-resistant depression and normalizes depression-related hyperconnectivity in the limbic system and frontal lobe. ClinicalTrials.gov: Treatment Resistant Depression (Pilot), NCT01179009.
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Decreased hyperconnectivity of the subgenual anterior cingulate cortex and the default mode network, as assessed through resting-state fMRI, were found to be associated with treatment response after a 96-h ketamine infusion.
“decreased hyperconnectivity of the subgenual anterior cingulate cortex and the default mode network, as assessed through resting-state fMRI, were found to be associated with treatment response after a 96-h ketamine infusion [211]”
From Ketamine in neuropsychiatric disorders: an update (2024) · cites this paper as [211]
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- Authors
- Siegel, J. S., Palanca, B. J. A., Ances, B. M., Kharasch, E. D., Schweiger, J. A., Yingling, M. D., Snyder, A. Z., Nicol, G. E., Lenze, E. J., & Farber, N. B.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- Siegel, Joshua S.
- ORCID
- Venue
- Psychopharmacology
- Published
- 2021-01-22
- Volume
- 238
- Issue
- 4
- Pages
- 1157-1169
- ISSN
- 0033-3158 (ISSN-L)
- 1432-2072
- PMC
- PMC7969576
- OpenAlex
- W3122632999
- Cited by
- 50
- References
- 74
- Citations by year
- 2026: 2 · 2025: 10 · 2024: 11 · 2023: 14 · 2022: 8 · 2021: 5
- FWCI
- 5.55
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Psychopharmacology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Sidney R. Baer, Jr. Foundation
- Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine in St. Louis
- Washington University Institute for Clinical and Translational Research (UL1TR000448)
- National Center for Advancing Translational Sciences (UL1TR002345)
- National Institute of Mental Health (R25 MH11247)
- National Institutes of Health (R01MH118031, R01NR015738, R01AG057680)
- 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, treatment-resistant depression, functional connectivity, subgenual anterior cingulate cortex, default mode network, hippocampus, amygdala, nucleus accumbens, medial thalamus, antidepressant response, clonidine, sustained remission, hippocampal volume
- MeSH terms
- Adolescent, Adult, Aged, Antidepressive Agents, Clonidine, Female, Gyrus Cinguli, Hallucinogens, Humans, Infusions, Intravenous, Ketamine, Limbic System, Magnetic Resonance Imaging, Male, Middle Aged, Nerve Net, Psychiatric Status Rating Scales, Sympatholytics, Treatment Outcome, Young Adult, Depressive Disorder, Treatment-Resistant
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