Ketamine induces multiple individually distinct whole-brain functional connectivity signatures.
Flora Moujaes, Jie Lisa Ji, Masih Rahmati, Joshua B. Burt, Charles Schleifer, Brendan Adkinson, Aleksandar Savič, Nicole Santamauro, Zailyn Tamayo, Caroline Diehl, Antonija Kolobaric, Morgan Flynn, Nathalie M. Rieser, Clara Fonteneau, Terry Camarro, Junqian Xu, Youngsun T. Cho, Grega Repovš, Sarah K. Fineberg, Peter T Morgan, Erich Seifritz, Franz X. Vollenweider, John H. Krystal, John D. Murray, Katrin H. Preller, Alan Anticevic
Elife April 17, 2024 DOI: 10.7554/elife.84173 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Single-blind placebo-controlled study Peer reviewed |
|---|---|
| Sample size | 40 |
| Population | Healthy participants |
| Intervention | Ketamine |
| Dose | initial bolus 0.23 mg/kg, continuous infusion 0.58 mg/kg/hr |
| Topics | Ketamine Esketamine |
| Keywords | Data reduction FMRI Gene expression Human Inter-individual variation Neuroscience research Personalized medicine Brain imaging Ketamine therapy |
| Citations | 23 |
| Registration | NCT03842800 |
| Key points | Ketamine's neural and behavioral effects are multi-dimensional and show robust inter-individual variability, with the principal neural gradient matching somatostatin and parvalbumin gene expression patterns. |
Abstract
Ketamine has emerged as one of the most promising therapies for treatment-resistant depression. However, inter-individual variability in response to ketamine is still not well understood and it is unclear how ketamine's molecular mechanisms connect to its neural and behavioral effects. We conducted a single-blind placebo-controlled study, with participants blinded to their treatment condition. 40 healthy participants received acute ketamine (initial bolus 0.23 mg/kg, continuous infusion 0.58 mg/kg/hr). We quantified resting-state functional connectivity via data-driven global brain connectivity and related it to individual ketamine-induced symptom variation and cortical gene expression targets. We found that: (i) both the neural and behavioral effects of acute ketamine are multi-dimensional, reflecting robust inter-individual variability; (ii) ketamine's data-driven principal neural gradient effect matched somatostatin (SST) and parvalbumin (PVALB) cortical gene expression patterns in humans, while the mean effect did not; and (iii) behavioral data-driven individual symptom variation mapped onto distinct neural gradients of ketamine, which were resolvable at the single-subject level. These results highlight the importance of considering individual behavioral and neural variation in response to ketamine. They also have implications for the development of individually precise pharmacological biomarkers for treatment selection in psychiatry. This study was supported by NIH grants DP5OD012109-01 (A.A.), 1U01MH121766 (A.A.), R01MH112746 (J.D.M.), 5R01MH112189 (A.A.), 5R01MH108590 (A.A.), NIAAA grant 2P50AA012870-11 (A.A.); NSF NeuroNex grant 2015276 (J.D.M.); Brain and Behavior Research Foundation Young Investigator Award (A.A.); SFARI Pilot Award (J.D.M., A.A.); Heffter Research Institute (Grant No. 1-190420) (FXV, KHP); Swiss Neuromatrix Foundation (Grant No. 2016-0111) (FXV, KHP); Swiss National Science Foundation under the framework of Neuron Cofund (Grant No. 01EW1908) (KHP); Usona Institute (2015 - 2056) (FXV). NCT03842800.
Comparable studies
Other randomized controlled trials on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Healthy human subjects recruited from the community | 1994 | Randomized controlled trial | n = 19 |
| Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial Patients with treatment-resistant major depression experiencing a major depressive episode | 2013 | Randomized controlled trial | n = 73 |
| Remifentanil-induced Postoperative Hyperalgesia and Its Prevention with Small-dose Ketamine Patients undergoing major abdominal surgery | 2005 | Randomized controlled trial | n = 75 |
| Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic Stress Disorder Patients with chronic PTSD related to a range of trauma exposures | 2014 | Randomized controlled trial | n = 41 |
| Ketamine-Induced Deficits in Auditory and Visual Context-Dependent Processing in Healthy Volunteers Healthy volunteers | 2000 | Single-blind placebo-controlled study | n = 20 |
Citations in the library
Cited by 13
- Exploring End-of-Life Experiences and Consciousness through the Lens of Psychedelics. ACS Pharmacology & Translational Science March 14, 2025
- Cortical high-frequency oscillations (≈ 110 Hz) in cats are state-dependent and enhanced by a subanesthetic dose of ketamine. Behavioural Brain Research January 5, 2025
- Connectome harmonic decomposition tracks the presence of disconnected consciousness during ketamine-induced unresponsiveness. British Journal of Anaesthesia April 1, 2025
- The entropic brain today Brain December 12, 2025
- Ketamine Improves Anhedonic Phenotypes Across Species: Translational Evidence From the Probabilistic Reward Task. Biological Psychiatry Global Open Science May 1, 2026
and 8 more in the library
Cites 32
- Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Archives of General Psychiatry March 1, 1994
- Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. The Lancet Psychiatry May 17, 2016
- Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial American Journal of Psychiatry August 28, 2013
- Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action Neuroreport December 1, 1998
- Safety and Efficacy of Lysergic Acid Diethylamide-Assisted Psychotherapy for Anxiety Associated With Life-threatening Diseases The Journal of Nervous and Mental Disease March 4, 2014
and 27 more in the library