Effects of ketamine and midazolam on resting state connectivity and comparison with ENIGMA connectivity deficit patterns in schizophrenia
Bhim M. Adhikari, Juergen Dukart, Joerg F. Hipp, Anna Forsyth, Rebecca McMillan, Suresh Muthukumaraswamy, Meghann C. Ryan, L. Elliot Hong, Simon B. Eickhoff, Neda Jahandshad, Paul M. Thompson, Laura M. Rowland, Peter Kochunov
Human Brain Mapping October 21, 2019 DOI: 10.1002/hbm.24838 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized, three-way, cross-over study Peer reviewed |
|---|---|
| Sample size | 30 |
| Population | Healthy male volunteers aged 19–37 years |
| Interventions | Ketamine Midazolam Placebo |
| Dose | subanesthetic |
| Duration | Three imaging sessions with 48 hr between sessions; each session consisted of a control period followed by infusion |
| Topics | Ketamine Esketamine |
| Keywords | Resting State FMRI Schizophrenia object-oriented programming Functional connectivity Connectome Midazolam Anesthesia |
| Citations | 24 |
| Key points | Ketamine-induced reductions in functional connectivity positively correlate with the pattern of connectivity deficits observed in schizophrenia. |
Abstract
Abstract Subanesthetic administration of ketamine is a pharmacological model to elicit positive and negative symptoms of psychosis in healthy volunteers. We used resting‐state pharmacological functional MRI (rsPhfMRI) to identify cerebral networks affected by ketamine and compared them to the functional connectivity (FC) in schizophrenia. Ketamine can produce sedation and we contrasted its effects with the effects of the anxiolytic drug midazolam. Thirty healthy male volunteers (age = 19–37 years) underwent a randomized, three‐way, cross‐over study consisting of three imaging sessions, with 48 hr between sessions. A session consisted of a control period followed by infusion of placebo or ketamine or midazolam. The ENIGMA rsfMRI pipeline was used to derive two long‐distance (seed‐based and dual‐regression) and one local (regional homogeneity, ReHo) FC measures. Ketamine induced significant reductions in the connectivity of the salience network (Cohen's d : 1.13 ± 0.28, p = 4.0 × 10 −3 ), auditory network ( d : 0.67 ± 0.26, p = .04) and default mode network (DMN, d : 0.63 ± 0.26, p = .05). Midazolam significantly reduced connectivity in the DMN ( d : 0.77 ± 0.27, p = .03). The effect sizes for ketamine for resting networks showed a positive correlation ( r = .59, p = .07) with the effect sizes for schizophrenia‐related deficits derived from ENIGMA's study of 261 patients and 327 controls. Effect sizes for midazolam were not correlated with the schizophrenia pattern ( r = −.17, p = .65). The subtraction of ketamine and midazolam patterns showed a significant positive correlation with the pattern of schizophrenia deficits ( r = .68, p = .03). RsPhfMRI reliably detected the shared and divergent pharmacological actions of ketamine and midazolam on cerebral networks. The pattern of disconnectivity produced by ketamine was positively correlated with the pattern of connectivity deficits observed in schizophrenia, suggesting a brain functional basis for previously poorly understood effects of the drug.
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 3
- Psilocybin-induced changes in brain network integrity and segregation correlate with plasma psilocin level and psychedelic experience. European Neuropsychopharmacology September 1, 2021
- Esketamine disinhibits brain networks in depression: Evidence from oscillatory and aperiodic activity. Progress in Neuro-Psychopharmacology and Biological Psychiatry July 5, 2025
- Resting-State Functional EEG Connectivity in Salience and Default Mode Networks and their Relationship to Dissociative Symptoms During NMDA Receptor Antagonism. Pharmacology, Biochemistry, and Behavior December 29, 2020
Cites 22
- Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Archives of General Psychiatry March 1, 1994
- Ketamine use: a review Addiction July 21, 2011
- Breakdown of within- and between-network Resting State Functional Magnetic Resonance Imaging Connectivity during Propofol-induced Loss of Consciousness Anesthesiology September 30, 2010
- Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic Stress Disorder JAMA Psychiatry April 16, 2014
- Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism American Journal of Psychiatry August 29, 2018
and 17 more in the library